Biocompatible and biodegradable elastomeric polymers

ABSTRACT

Disclosed herein are biocompatible and biodegradable polymers comprising one or more ECM-mimetic peptides and one or more biodegradable moieties, wherein the moieties do not comprise an amino acid or residue thereof. Further disclosed herein are methods for making and using the disclosed biocompatible polymers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 61/051,987, filed May 9, 2008, which is incorporated byreference herein in its entirety.

FIELD

Disclosed herein are biocompatible and biodegradable polymers comprisingone or more ECM-mimetic peptides. Further disclosed herein are methodsfor making and using the disclosed biocompatible polymers.

BACKGROUND

Extracellular matrix (ECM) proteins are important modulators of thecellular microenvironment. The interaction of cell-ECM is critical inregulation of cellular functions such as adhesion, migration,proliferation and differentiation. The disruption of cell-ECM structureaffects the functionality of the cell and, hence, may result inapoptosis. Because of this reason, the naturally-occurring ECM proteinshave been considered in medical applications such as tissue engineeringand wound healing. Although the size of naturally-occurring ECM proteinsranges to upwards of several hundreds of kilodaltons, the functionalityof these proteins arises generally from the presence of specific peptidesequences that are present within the ECM protein. One or more suchsequences may be present and repeated through the ECM protein. As oneexample, a repeating pentapeptide sequence of Val-Pro-Gly-Val-Gly [SEQID NO: 1] in elastin, the second most common ECM protein, attributes toits elasticity. Therefore, the polymers of these pentapeptides arereported to have potential in medical application. (See, Dan W. Urry andAsima Pattanaik, “Elastic Protein-based Materials in TissueReconstruction,” Artificial Organs, 831:32-46, 1997, and Dan W. Urry,Asima Pattanaik, Jie Xu, T. Cooper Woods, David T. McPherson and TimothyM. Parker, “Elastic Protein-based Polymers in Soft Tissue Augmentationand Generation,” J. Biomater. Sci. Polymer Edn., 9(10):1015-1048, 1998.)

The biological half-life of elastin protein is in the order of 70 years.The polymer containing pentapeptide, Val-Pro-Gly-Val-Gly, is expected toremain in a folded state at biological temperature hence it is alsonaturally resistant to the proteolytic degradation. It would be mostadvantageous for any scaffolding material to have the capacity todegrade once the natural tissue has been reconstructed at the site andthe presence of the polymer is no longer needed. Therefore, addition ofa degradable moiety or functionality to such polymers would have greatpotential for applications such as tissue engineering; wound healing,coatings, and drug delivery. By controlling the frequency anddegradation half-life of the degradable functionality, these polymerscan be engineered to have half-lives from a few days to years.

SUMMARY

In accordance with the purposes of the disclosed materials, compounds,compositions, articles, and methods, as embodied and broadly describedherein, the disclosed subject matter, in one aspect, relates tocompositions and methods for preparing and using such compositions. In afurther aspect, the disclosed subject matter relates to biocompatiblepolymers comprising:

-   -   a) one or more ECM-mimetic peptides; and    -   b) one or more biodegradable moieties, wherein the moieties do        not comprise an amino acid or residue thereof,        wherein the polymers have a weight average molecular weight of        from about 1,000 Da to about 2,000,000 Da. Also disclosed are        methods for using the disclosed biocompatible polymers. Further        disclosed are methods for preparing the disclosed biocompatible        polymers.

Additional advantages will be set forth in part in the description thatfollows, and in part will be obvious from the description, or may belearned by practice of the aspects described below. The advantagesdescribed below will be realized and attained by means of the elementsand combinations particularly pointed out in the appended claims. It isto be understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive.

DETAILED DESCRIPTION

The materials, compounds, compositions, articles, devices, and methodsdescribed herein can be understood more readily by reference to thefollowing detailed description of specific aspects of the disclosedsubject matter and the Examples included therein.

Before the present copolymers, polymer admixtures, compounds,compositions, and/or methods are disclosed and described, it is to beunderstood that the aspects described herein are not limited to specificcompounds, synthetic methods, or uses as such can, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular aspects only and, unless specificallydefined herein, is not intended to be limiting.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

GENERAL DEFINITIONS

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

Throughout this specification, unless the context requires otherwise,the word “comprise,” or variations such as “comprises” or “comprising,”will be understood to imply the inclusion of a stated integer or step orgroup of integers or steps but not the exclusion of any other integer orstep or group of integers or steps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint.

By “contacting” is meant the physical contact of at least one substanceto another substance.

By “sufficient amount” and “sufficient time” means an amount and timeneeded to achieve the desired result or results, e.g., dissolve aportion of the polymer.

Biological and Chemical Definitions

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

“Biocompatible” as used herein means the biological response to thematerial or device is appropriate for the device's intended applicationin vivo. Any metabolites of these materials should also bebiocompatible.

“Amino acid” as used herein means α-amino acids (as identified asstandard amino acids in Voet and Voet, Biochemistry, John Wiley andSons, 1990) including alanine, arginine, asparagine, aspartic acid,cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, and valine, and also β- and γ-amino acids.

“Biodegradable” generally refers to a biocompatible material that willdegrade or erode under physiologic conditions to smaller units orchemical species that are, themselves, biocompatible or non-toxic to thesubject and capable of being metabolized, eliminated, or excreted by thesubject.

“Bioactive agent” is used herein to include a compound of interestcontained in or on the polymer such as therapeutic or biologicallyactive compounds that may be used internally or externally as a medicinefor the treatment, diagnosis, cure, or prevention of a disease ordisorder. Examples can include, but are not limited to, drugs,small-molecule drugs, peptides, proteins, oligonucleotides, imagingagents, contrast agents. “Bioactive agent” includes a single such agentand is also intended to include a plurality of bioactive agentsincluding, for example, combinations of two or more bioactive agents.

“Molecular weight” as used herein, unless otherwise specified, refersgenerally to the relative average molecular weight of the bulk polymer.While in practice molecular weight can be estimated or characterized invarious ways, including gel permeation chromatography (GPC) or capillaryviscometry, molecular weights referred to herein are as measured by GPC.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixtures.

Enantiomeric species can exist in different isomeric or enantiomericforms. Unless otherwise specified, enantiomeric species discussed hereinwithout reference to their isomeric form shall include all variousisomeric forms as well as racemic or scalemic mixtures of isomericforms. For example, reference to lactic acid shall herein includeL-lactic acid, D-lactic acid, and racemic or scalemic mixtures of the L-and D-isomers of lactic acid; reference to lactide shall herein includeL-lactide, D-lactide, and DL-lactide (where DL-lactide refers to racemicor scalemic mixtures of the L- and D-isomers of lactide); similarly,reference to poly(lactide) shall herein include poly(L-lactide),poly(D-lactide) and poly(DL-lactide); similarly, reference topoly(lactide-co-glycolide) will herein includepoly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), andpoly(DL-lactide-co-glycolide); and so on.

The terms “percent (%) sequence similarity,” “percent (%) sequenceidentity,” and the like, generally refer to the degree of identity orcorrespondence between different amino acid sequences of proteins orpeptides that may or may not share a common evolutionary origin.Sequence identity can be determined using any of a number of publiclyavailable sequence comparison algorithms, such as BLAST, FASTA, etc. Todetermine the percent identity between two amino acid sequences, thesequences are aligned for optimal comparison purposes. The percentidentity between the two sequences is a function of the number ofidentical positions shared by the sequences (i.e., percentidentity=number of identical positions/total number of positions (e.g.,overlapping positions)×100). In one embodiment, the two sequences are,or are about, of the same length. The percent identity between twosequences can be determined using techniques similar to those describedbelow, with or without allowing gaps. In calculating percent sequenceidentity, typically exact matches are counted.

The determination of percent identity between two sequences can beaccomplished using a mathematical algorithm. A non-limiting example of amathematical algorithm utilized for the comparison of two sequences isthe algorithm of Karlin and Altschul, Proc. Natl. Acad. Sci. USA87:2264, 1990, modified as in Karlin and Altschul, Proc. Natl. Acad.Sci. USA 90:5873-5877, 1993. Such an algorithm is incorporated into theNBLAST and XBLAST programs of Altschul et al., J. Mol. Biol. 215:403,1990. BLAST protein searches can be performed with the XBLAST program,score=100, wordlength=12, to obtain amino acid sequences homologous toprotein sequences of the invention. Another non-limiting example of amathematical algorithm utilized for the comparison of sequences is thealgorithm of Myers and Miller, CABIOS 4:11-17, 1988. Such an algorithmis incorporated into the ALIGN program (version 2.0), which is part ofthe GCG sequence alignment software package. When utilizing the ALIGNprogram for comparing amino acid sequences, a PAM 120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4 can be used.In one embodiment, the percent identity between two amino acid sequencesis determined using the algorithm of Needleman and Wunsch (J. Mol. Biol.48:444-453, 1970), using either a Blossum 62 matrix or a PAM250 matrix,a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2,3, 4, 5, or 6. Sequence similarity can also be determined by inspection.

As disclosed herein there are numerous variants of proteins and peptides(e.g., ECM-mimetic peptides) that are contemplated herein. In additionto the ECM mimetic peptide variants, there are derivatives of thesepeptides that also function in the disclosed methods and compositions.Protein variants and derivatives are well understood to those of skillin the art and can involve amino acid sequence modifications. Forexample, amino acid sequence modifications typically fall into one ormore of three classes: substitutional, insertional, or deletionalvariants. Insertions include amino and/or carboxyl terminal fusions aswell as intrasequence insertions of single or multiple amino acidresidues. Insertions ordinarily will be smaller insertions than those ofamino or carboxyl terminal fusions, for example, on the order of one tofour residues. Deletions are characterized by the removal of one or moreamino acid residues from the protein sequence. Typically, no more thanfrom about 2 to about 6 residues are deleted at any one site within thepeptide/protein molecule. These variants can ordinarily be prepared bysite specific mutagenesis of nucleotides in the DNA encoding theprotein, thereby producing DNA encoding the variant, and thereafterexpressing the DNA in recombinant cell culture. Techniques for makingsubstitution mutations at predetermined sites in DNA having a knownsequence are well known, for example M13 primer mutagenesis and PCRmutagenesis. Accordingly, recombinant technologies can be used for theproduction of the disclosed peptides. However, chemical synthesis can betypically used for a relatively short peptide/protein such as theECM-mimetic peptides disclosed herein. Amino acid substitutions aretypically of single amino acid residues, but can occur at a number ofdifferent locations at once; insertions usually can be on the order offrom about 1 to about 10 amino acid residues; and deletions can rangefrom about 1 to about 30 residues. Deletions or insertions can be madein adjacent pairs, i.e., a deletion of 2 amino acid residues orinsertion of 2 amino acid residues. Substitutions, deletions, insertionsor any combination thereof may be combined to arrive at a finalconstruct. Substitutional variants are those in which at least one aminoacid residue has been removed and a different residue inserted in itsplace. Such substitutions generally are made in accordance with thefollowing Table 1 and are referred to as “conservative substitutions.”

TABLE 1 Amino Acid Substitutions Original Residue Exemplary ConservativeSubstitutions, others are known in the art. Ala

 Ser Arg

 Lys; Gln Asn

 Gln; His Asp

 Glu Cys

 Ser Gln

 Asn or Lys Glu

 Asp Gly

 Pro His

 Asn or Gln Ile

 Leu or Val Leu

 Ile or Val Lys

 Arg or Gln Met

 Leu or Ile Phe

 Met, Leu, or Tyr Ser

 Thr Thr

 Ser Trp

 Tyr Tyr

 Trp or Phe Val

 Ile or Leu

Substantial changes in function can be made by selecting substitutionsthat are less conservative than those in Table 1, i.e., selectingresidues that differ more significantly in their effect on maintaining(a) the structure of the polypeptide backbone in the area of thesubstitution, for example as a sheet or helical conformation, (b) thecharge or hydrophobicity of the molecule at the target site or (c) thebulk of the side chain. The substitutions which in general are expectedto produce the greatest changes in the protein properties will be thosein which (a) a hydrophilic residue, e.g., seryl or threonyl, issubstituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl,phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substitutedfor (or by) any other residue; (c) a residue having an electropositiveside chain, e.g., lysyl, arginyl, or histidyl, is substituted for (orby) an electronegative residue, e.g., glutamyl or aspartyl; or (d) aresidue having a bulky side chain, e.g., phenylalanine, is substitutedfor (or by) one not having a side chain, e.g., glycine, in this case,(e) by increasing the number of sites for sulfation and/orglycosylation.

For example, the replacement of one amino acid residue with another thatis biologically and/or chemically similar is known to those skilled inthe art as a conservative substitution. For example, a conservativesubstitution would be replacing one hydrophobic residue for another orone polar residue for another. The substitutions include combinationssuch as Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg;and Phe, Tyr. Such conservatively substituted variations of eachexplicitly disclosed sequence are included within the polypeptidesprovided herein.

Substitutional or deletional mutagenesis can be employed to insert sitesfor N-glycosylation (Asn-X-Thr/Ser) or O-glycosylation (Ser or Thr).Deletions of cysteine or other labile residues also may be desirable.Deletions or substitutions of potential proteolysis sites, e.g., Arg,can be accomplished, for example, by deleting one of the basic residuesor substituting one by glutaminyl or histidyl residues.

Certain post-translational derivatizations are the result of the actionof recombinant host cells on the expressed polypeptide. Glutaminyl andasparaginyl residues are frequently post-translationally deamidated tothe corresponding glutamyl and asparyl residues. Alternatively, theseresidues are deamidated under mildly acidic conditions. Otherpost-translational modifications include hydroxylation of proline andlysine, phosphorylation of hydroxyl groups of seryl or threonylresidues, methylation of the O-amino groups of lysine, arginine, andhistidine side chains (Creighton, Proteins: Structure and MolecularProperties, W. H. Freeman & Co., San Francisco pp. 79-86 (1983), whichis incorporated by reference herein for its material onpost-translational derivatizations), acetylation of the N-terminal amineand, in some instances, amidation of the C-terminal carboxyl.

It is understood that one way to define the variants, derivatives, andanalogs of the peptides and proteins disclosed herein is throughdefining the variants, derivatives, and analogs in terms ofhomology/identity to specific known sequences. For example, SEQ ID NO: 1sets forth the particular sequence of an ECM mimetic peptide.Specifically disclosed are variants, derivatives, and analogs of theseand other peptides and proteins herein disclosed which have at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence similarityto the stated sequence. Those of skill in the art readily understand howto determine the sequence similarity of two proteins, as is disclosedmore fully supra.

It is further understood that there are numerous amino acid and peptideanalogs that can be incorporated into the disclosed compositions. Forexample, there are numerous D amino acids or amino acids which have adifferent functional substituent then the amino acids described above.The opposite stereo isomers of naturally occurring peptides aredisclosed, as well as the stereo isomers of peptide analogs. These aminoacids can readily be incorporated into polypeptide chains by chargingtRNA molecules with the amino acid of choice and engineering geneticconstructs that utilize, for example, amber codons, to insert the analogamino acid into a peptide chain in a site specific way (Thorson, et al.,Methods in Molec Biol 77:43-73, 1991, Zoller, Curr Opin Biotech3:348-354, 1992; Ibba, Biotech & Gen Eng Rev 13:197-216, 1995, Cahill,et al., TIBS 14(10):400-403, 1989; Benner, TIB Tech 12:158-163, 1994;Ibba and Hennecke, Bio/technology 12:678-682, 1994, all of which areincorporated by reference herein for their material related to aminoacid analogs).

It is further contemplated that molecules can be synthesized thatresemble the peptides disclosed herein, but which are not connected viaa natural peptide linkages. For example, peptide analogs can havelinkages for amino acids or amino acid analogs that include —CH₂NH—,—CH₂S—, —CH₂—CH₂—, —CH═CH— (cis and trans), —COCH₂—, —CH(OH)CH₂—, and—CH₂SO— (These and others can be found in Spatola, in Chemistry andBiochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983); Spatola, Vega Data (March 1983),Vol. 1, Issue 3, Peptide Backbone Modifications (general review);Morley, Trends Pharm Sci (1980) pp. 463-468; Hudson et al., Int J PeptProt Res 14:177-185, 1979 (—CH₂NH—, —CH₂CH₂—); Spatola et al., Life Sci,38:1243-1249, 1986 (—CH₂S—); Hann, J Chem Soc, Perkin Trans 1,307-314,1982 (—CH═CH—, cis and trans); Almquist, et al., J Med Chem23:1392-1398, 1980 (—COCH₂—); Jennings-White et al., Tetrahedron Lett23:2533, 1982 (—COCH₂—); Szelke et al., European Appln, EP 45665 CA(1982)(—CH(OH)CH₂—); Holladay et al., Tetrahedron Lett 24:4401-4404,1983 (—CH(OH)CH₂—); and Hruby Life Sci 31:189-199, 1982 (—CH₂S—); eachof which is incorporated by reference herein for its material regardingpeptide analogs, mimetics, and non-peptide linkages). Also, it isunderstood that peptide analogs can have more than one atom between thebond atoms, such as β-alanine, γ-aminobutyric acid, and the like.

Amino acid analogs and peptide analogs often have enhanced or desirableproperties, such as, more economical production, greater chemicalstability, enhanced pharmacological properties (half-life, absorption,potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum ofbiological activities), reduced antigenicity, and others. For example,D-amino acids and β-amino acids can be used to generate more stablepeptides, because these amino acids are not recognized by peptidases andsuch. Systematic substitution of one or more amino acids of a consensussequence with a D- or β-amino acid of the same type (e.g., D-lysine inplace of L-lysine or β-alanine in place of alanine) can be used togenerate more stable peptides. Cysteine residues can be used to cyclizeor attach two or more peptides together. This can be beneficial toconstrain peptides into particular conformations (Rizo and Gierasch, AnnRev Biochem 61:387, 1992).

Reference will now be made in detail to specific aspects of thedisclosed materials, compounds, compositions, components, devices,articles, and methods, examples of which are illustrated in thefollowing description and examples, and in the figures and theirprevious and following description.

Biocompatible Polymers

The disclosed biocompatible polymers have several desirable attributes,for example, elasticity, flexibility, and strength. Thus, they can havemodified properties when compared to a naturally occurring ECM-protein,while still undergoing bio-degradation. The ECM-mimetic peptide sequencedisclosed herein can be an elastin-mimetic, a fibrinogen-mimetic, afibroin-mimetic, a silk-mimetic, a collagen-mimetic, a keratin-mimetic,or a mixture of one or more other mimetics together with theaforementioned.

The disclosed biocompatible polymers can comprise:

-   -   a) one or more ECM-mimetic peptides; and    -   b) one or more biodegradable linkers wherein the linker does not        comprise an amino acid;        wherein the polymer has a weight average molecular weight of        from about 1,000 Da to about 2,000,000 Da. In one embodiment,        the polymer has a weight average molecular weight of from about        1,000 Da to about 2,000,000 Da. In another embodiment, the        polymer has a weight average molecular weight of from about        1,000 Da to about 20,000 Da. In a further embodiment, the        polymer has a weight average molecular weight of from about        1,000 Da to about 10,000 Da. In a yet further embodiment, the        polymer has a weight average molecular weight of from about        10,000 Da to about 100,000 Da. In a still further embodiment,        the polymer has a weight average molecular weight of from about        10,000 Da to about 50,000 Da. In a yet another embodiment, the        polymer has a weight average molecular weight of from about        5,000 Da to about 20,000 Da. While in a yet another embodiment,        the polymer has a weight average molecular weight of from about        10,000 Da to about 20,000 Da. In a still yet further embodiment,        the polymer has a weight average molecular weight of from about        50,000 Da to about 200,000 Da. In yet further embodiments, the        polymer has a weight average molecular weight of from about        100,000 to about 400,000 Da, from about 400,000 to about 800,000        Da, or from about 800,000 to about 2,000,000 Da.

The disclosed ECM-mimetic peptides comprise residues of amino acids, forexample, an α-amino acid, a β-amino acid, a γ-amino acid, and the like.In addition, the amino acids can be chiral, for example, (L)-amino aids,(D)-amino acids, racemic mixtures, or mixtures wherein one opticalisomer is enhanced, for example, a 60:40 ratio of one enantiomer overthe other. In addition, for amino acids that exist in diastereomericform, inter alia, threonine, any diastereomeric form or mixtures thereofcan be used to form the disclosed ECM-mimetic peptides.

One aspect of the disclosed biocompatible polymers relates to polymershaving the formula:

wherein Mim is an ECM-mimetic peptide having the formula:

-[Xaa-Xbb-Xcc-Xdd-Xee]_(x)-

wherein Xaa, Xbb, Xcc, Xdd, and Xee are each independently an amino acidresidue chosen from:i) glycine or a conservative substitution thereof,ii) valine or a conservative substitution thereof, andiii) proline or a conservative substitution thereof,BioDeg is the non-amino acid residue containing biodegradable moiety;the index x is an integer from 1 to 30;the index y is an integer from 1 to 10; andthe index z is an integer from 1 to 2000.

In one iteration of this embodiment, the index x is 1. In anotheriteration, the index x is an integer from 2 to 10. In a furtheriteration, the index x is an integer from 2 to 6. In a still furtheriteration, the index x is an integer from 2 to 5. In a still yet furtheriteration, the index x is an integer from 2 to 4, 5 to 10, 10 to 20, 20to 30, 15 to 30, 2 to 20, and the like. In another further iteration,the index x is an integer chosen from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,or 30, where any of the stated values can for the upper or lowerendpoint of a range. Non-limiting examples of this embodiment includesthe index x equal to 4, the index x equal to 5, and the index x equal to6.

In one iteration of this embodiment, the index y is 1. In anotheriteration, the index y is an integer from 2 to 6. In a furtheriteration, the index y is an integer from 3 to 5. In a still furtheriteration, the index y is an integer from 2 to 5. In a still yet furtheriteration, the index y is an integer from 2 to 4. In another furtheriteration, the index y is an integer chosen from 1, 2, 3, 4, 5, 6, 7, 8,9, or 10, where any of the stated values can for the upper or lowerendpoint of a range.

The index z is an integer from 1 to 2000. The index z has a value suchthat the polymer has a weight average molecular weight of from about1,000 Da to about 2,000,000 Da. In one embodiment, the index z has avalue such that the polymer has a weight average molecular weight offrom about 1,000 Da to about 2,000,000 Da. In another embodiment, theindex z has a value such that the polymer has a weight average molecularweight of from about 1,000 Da to about 20,000 Da. In a furtherembodiment, the index z has a value such that the polymer has a weightaverage molecular weight of from about 1,000 Da to about 10,000 Da. In ayet further embodiment, the index z has a value such that the polymerhas a weight average molecular weight of from about 10,000 Da to about100,000 Da. In a still further embodiment, the index z has a value suchthat the polymer has a weight average molecular weight of from about10,000 Da to about 50,000 Da. In a yet another embodiment, the index zhas a value such that the polymer has a weight average molecular weightof from about 5,000 Da to about 20,000 Da. While in a yet anotherembodiment, the index z has a value such that the polymer has a weightaverage molecular weight of from about 10,000 Da to about 20,000 Da. Ina still yet further embodiment, the index z has a value such that thepolymer has a weight average molecular weight of from about 50,000 Da toabout 200,000 Da.

Another aspect of the disclosed polymers relates to polymers thatfurther comprise a biodegradable or non-biodegradable linking group, L,that serves to link the one or more ECM-mimetic peptides (Mim) and theone or more biodegradable moieties (BioDeg). One embodiment of thisaspect relates to polymers having the formula:

wherein the index y and the index z are as defined herein. Anotherembodiment of this aspect relates to polymers having the formula:

wherein the index y and the index z are as defined herein. A furtherembodiment of this aspect relates to polymers having the formula:

wherein the index y and the index z are as defined herein. A yet furtherembodiment of this aspect relates to polymers having the formula:

wherein the index y and the index z are as defined herein.

A still further embodiment of this aspect relates to polymers having theformula:

wherein the index y and the index z are as defined herein.

Extracellular Matrix (ECM) Mimetic Peptides

The disclosed biocompatible and/or biodegradable polymers can compriseone or more segments of an ECM-mimetic peptide (identified as “Mim” inthe formulae herein)(examples are provided herein). The disclosed one ormore ECM-mimetic peptides can be any peptide sequence that repeatsthroughout an ECM protein and that provides for a characteristicproperty of the ECM protein. For example, the ECM protein elastin ischaracterized by a highly elastic property. This elastic property isknown to be derived from a peptide sequence that is repeated throughoutthe protein. In the case of elastin, this repeating peptide sequenceprovides a characteristic beta-turn structure to the elastin protein.The peptide sequence (the ECM-mimetic peptide sequence) comprises arepeating sequence of 4 or more amino acids based on G, V, and P. Thus,examples of the elastin ECM-mimetic peptide sequence include, but arenot limited to, VPGG, GxxP, GxGVP, VPGxG, GVGVP, GVGVxP, and so on wherex can be selected from various other amino acids without losing theECM-mimetic character of this sequence (for example, x can be chosenfrom valine, lysine, histidine, glutamic acid, arginine, aspartic acid,serine, tryptophan, tyrosine, phenylalanine, leucine, glutamine,asparagine, cysteine, or methionine; x is more preferably valine orlysine). Similarly, the ECM-mimetic peptide sequence for silk cancomprise GAGAGS. In keeping with this explanation, an ECM mimeticpeptide can described as being an elastin mimetic, a fibrinogen-mimetic,a fibroin-mimetic, a silk-mimetic, a collagen-mimetic, akeratin-mimetic, or a mixture thereof.

In one aspect, the ECM mimetic peptide (Mim) may comprise 3 amino acids,4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, and thelike. As such, the disclosed biocompatible polymers comprise one or moreMim units, for example, having the formula:

-[Xaa-Xbb-Xcc]_(x)—; or

-[Xaa-Xbb-Xcc-Xdd]_(x)—; or

-[Xaa-Xbb-Xcc-Xdd-Xee]_(x)—; or

-[Xaa-Xbb-Xcc-Xdd-Xee-Xff]_(x)—; or

-[Xaa-Xbb-Xcc-Xdd-Xee-Xff-Xgg]_(x)-.

where the amino acids comprising the Mim units are comprised ofECM-mimetic peptide sequences having 3, 4, 5, 6, 7, or more amino acids.

One category of the disclosed biocompatible polymers comprises one ormore Mim units having the formula:

-[Xaa-Xbb-Xcc-Xdd-Xee]_(x)-

wherein Xaa, Xbb, Xcc, Xdd, and Xee are each independently an amino acidresidue chosen from:

i) glycine or a conservative substitution thereof,

ii) valine or a conservative substitution thereof, and

iii) proline or a conservative substitution thereof

wherein Xaa, Xbb, Xcc, Xdd, and Xee represent amino acid residuesindependently chosen from:

i) glycine or conservative substitutions thereof,

ii) valine or conservative substitutions thereof, and

iii) proline or conservative substitutions thereof.

For the purposes of the present disclosure, the conservativesubstitutions include alanine as a substitute for glycine (Ala for Gly),leucine and isoleucine as substitutes for valine (Leu and Ile for Val),and aziridine-2-carboxylic acid, azetidine-2-carboxylic acid,piperidine-2-carboxylic acid, and piperidine-3-carboxylic acid assubstitutes for proline (Aza, Aze, 2-Pip, and 3-Pip for Pro).

In one embodiment of this category wherein the index x is equal to 1,non-limiting examples of ECM-mimetic peptides are chosen from:

i) Val-Pro-Gly-Val-Gly; [SEQ ID NO: 1] ii) Val-Pro-Gly-Gly-Val; [SEQ IDNO: 2] iii) Val-Pro-Val-Gly-Gly; [SEQ ID NO: 3] iv) Gly-Pro-Gly-Val-Val;[SEQ ID NO: 4] v) Gly-Pro-Val-Gly-Val; [SEQ ID NO: 5] vi)Gly-Pro-Val-Val-Gly; [SEQ ID NO: 6] vii) Pro-Val-Gly-Val-Gly; [SEQ IDNO: 7] viii) Pro-Val-Gly-Gly-Val; [SEQ ID NO: 8] ix)Pro-Val-Val-Gly-Gly; [SEQ ID NO: 9] x) Pro-Gly-Gly-Val-Val; [SEQ ID NO:10] xi) Pro-Gly-Val-Gly-Val; [SEQ ID NO: 11] xii) Pro-Gly-Val-Val-Gly;[SEQ ID NO: 12] xiii) Val-Gly-Pro-Val-Gly; [SEQ ID NO: 13] xiv)Val-Gly-Pro-Gly-Val; [SEQ ID NO: 14] xv) Val-Val-Pro-Gly-Gly; [SEQ IDNO: 15] xvi) Gly-Gly-Pro-Val-Val; [SEQ ID NO: 16] xvii)Gly-Val-Pro-Gly-Val; [SEQ ID NO: 17] xviii) Gly-Val-Pro-Val-Gly; [SEQ IDNO: 18] xix) Val-Gly-Val-Pro-Gly; [SEQ ID NO: 19] xx)Val-Gly-Gly-Pro-Val; [SEQ ID NO: 20] xxi) Val-Val-Gly-Pro-Gly; [SEQ IDNO: 21] xxii) Gly-Gly-Val-Pro-Val; [SEQ ID NO: 22] xxiii)Gly-Val-Gly-Pro-Val; [SEQ ID NO: 23] xxiv) Gly-Val-Val-Pro-Gly; [SEQ IDNO: 24] xxv) Val-Gly-Val-Gly-Pro; [SEQ ID NO: 25] xxvi)Val-Gly-Gly-Val-Pro; [SEQ ID NO: 26] xxvii) Val-Val-Gly-Gly-Pro; [SEQ IDNO: 27] xxviii) Gly-Gly-Val-Val-Pro; [SEQ ID NO: 28] xxix)Gly-Val-Gly-Val-Pro; [SEQ ID NO: 29] and xxx) Gly-Val-Val-Gly-Pro. [SEQID NO: 30]

In another embodiment of this category wherein the index x is equal to2, non-limiting examples of ECM-mimetic peptides are chosen from:

i) Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly; [SEQ ID NO: 31] ii)Val-Pro-Gly-Gly-Val-Val-Pro-Gly-Gly-Val; [SEQ ID NO: 32] iii)Val-Pro-Val-Gly-Gly-Val-Pro-Val-Gly-Gly; [SEQ ID NO: 33] iv)Gly-Pro-Gly-Val-Val-Gly-Pro-Gly-Val-Val; [SEQ ID NO: 34] v)Gly-Pro-Val-Gly-Val-Gly-Pro-Val-Gly-Val; [SEQ ID NO: 35] vi)Gly-Pro-Val-Val-Gly-Gly-Pro-Val-Val-Gly; [SEQ ID NO: 36] vii)Pro-Val-Gly-Val-Gly-Pro-Val-Gly-Val-Gly; [SEQ ID NO: 37] viii)Pro-Val-Gly-Gly-Val-Pro-Val-Gly-Gly-Val; [SEQ ID NO: 38] ix)Pro-Val-Val-Gly-Gly-Pro-Val-Val-Gly-Gly; [SEQ ID NO: 39] x)Pro-Gly-Gly-Val-Val-Pro-Gly-Gly-Val-Val; [SEQ ID NO: 40] xi)Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val; [SEQ ID NO: 41] xii)Pro-Gly-Val-Val-Gly-Pro-Gly-Val-Val-Gly; [SEQ ID NO: 42] xiii)Val-Gly-Pro-Val-Gly-Val-Gly-Pro-Val-Gly; [SEQ ID NO: 43] xiv)Val-Gly-Pro-Gly-Val-Val-Gly-Pro-Gly-Val; [SEQ ID NO: 44] xv)Val-Val-Pro-Gly-Gly-Val-Val-Pro-Gly-Gly; [SEQ ID NO: 45] xvi)Gly-Gly-Pro-Val-Val-Gly-Gly-Pro-Val-Val; [SEQ ID NO: 46] xvii)Gly-Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Val; [SEQ ID NO: 47] xviii)Gly-Val-Pro-Val-Gly-Gly-Val-Pro-Val-Gly; [SEQ ID NO: 48] xix)Val-Gly-Val-Pro-Gly-Val-Gly-Val-Pro-Gly; [SEQ ID NO: 49] xx)Val-Gly-Gly-Pro-Val-Val-Gly-Gly-Pro-Val; [SEQ ID NO: 50] xxi)Val-Val-Gly-Pro-Gly-Val-Val-Gly-Pro-Gly; [SEQ ID NO: 51] xxii)Gly-Gly-Val-Pro-Val-Gly-Gly-Val-Pro-Val; [SEQ ID NO: 52] xxiii)Gly-Val-Gly-Pro-Val-Gly-Val-Gly-Pro-Val; [SEQ ID NO: 53] xxiv)Gly-Val-Val-Pro-Gly-Gly-Val-Val-Pro-Gly; [SEQ ID NO: 54] xxv)Val-Gly-Val-Gly-Pro-Val-Gly-Val-Gly-Pro; [SEQ ID NO: 55] xxvi)Val-Gly-Gly-Val-Pro-Val-Gly-Gly-Val-Pro; [SEQ ID NO: 56] xxvii)Val-Val-Gly-Gly-Pro-Val-Val-Gly-Gly-Pro; [SEQ ID NO: 57] xxviii)Gly-Gly-Val-Val-Pro-Gly-Gly-Val-Val-Pro; [SEQ ID NO: 58] xxix)Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val-Pro; [SEQ ID NO: 59] and xxx)Gly-Val-Val-Gly-Pro-Gly-Val-Val-Gly-Pro. [SEQ ID NO: 60]

Another category of ECM-mimetic peptides includes peptides wherein aparticular ECM-peptide mimetic sequence is found within an ECM-peptidethat comprises amino acids chosen from glycine, alanine, valine,leucine, isoleucine, and proline, for example:

i) Gly-Val-Pro-Gly-Val-Gly-Gly; [SEQ ID NO: 61] ii)Pro-Gly-Val-Pro-Gly-Val-Gly-Gly; [SEQ ID NO: 62] iii)Gly-Val-Pro-Gly-Val-Gly-Leu-Ala; [SEQ ID NO: 63] iv)Val-Gly-Val-Pro-Gly-Val-Gly-Ile-Gly; [SEQ ID NO: 64] v)Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Gly; [SEQ ID NO: 65] vi)Gly-Val-Pro-Gly-Val-Gly-Leu-Leu; [SEQ ID NO: 66] vii)Gly-Gly-Gly-Val-Pro-Gly-Val-Gly-Gly-Gly; [SEQ ID NO: 67] viii)Gly-Gly-Val-Pro-Gly-Val-Gly-Gly-Ala-Ala; [SEQ ID NO: 68] ix)Pro-Pro-Gly-Val-Pro-Gly-Val-Gly-Gly-Gly-Pro; [SEQ ID NO: 69] x)Ala-Val-Pro-Gly-Val-Gly-Ala; [SEQ ID NO: 70] xi)Ala-Ala-Val-Pro-Gly-Val-Gly-Ala; [SEQ ID NO: 71] xii)Ala-Val-Pro-Gly-Val-Gly-Ala-Ala; [SEQ ID NO: 72] xiii)Ala-Ala-Val-Pro-Gly-Val-Gly-Ala-Ala; [SEQ ID NO: 73] xiv)Ala-Leu-Ala-Val-Pro-Gly-Val-Gly-Ala; [SEQ ID NO: 74] xv)Ala-Val-Pro-Gly-Val-Gly-Ala-Ile-Ile; [SEQ ID NO: 75] xvi)Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Gly-Val; [SEQ ID NO: 76] xvii)Ala-Ala-Val-Pro-Gly-Val-Gly-Ala-Ala-Ala; [SEQ ID NO: 77] and xviii)Ala-Ala-Ala-Val-Pro-Gly-Val-Gly-Ala-Ala-Ala; [SEQ ID NO: 78]

Another embodiment of this category relates to ECM-mimetic peptidescomprising a plurality of receptor sequences. For example, ECM-mimeticpeptides having the formulae:

[(Xaa-Xbb-Xcc-Xdd-Xee)]₃;

[(Xaa-Xbb-Xcc-Xdd-Xee)]₄;

[(Xaa-Xbb-Xcc-Xdd-Xee)]₅; or

[(Xaa-Xbb-Xcc-Xdd-Xee)]₆;

wherein [(Xaa-Xbb-Xcc-Xdd-Xee)] comprises one or more sequences chosenfrom:

i) Val-Pro-Gly-Val-Gly; [SEQ ID NO: 1] ii) Val-Pro-Gly-Gly-Val; [SEQ IDNO: 2] iii) Val-Pro-Val-Gly-Gly; [SEQ ID NO: 3] iv) Gly-Pro-Gly-Val-Val;[SEQ ID NO: 4] v) Gly-Pro-Val-Gly-Val; [SEQ ID NO: 5] vi)Gly-Pro-Val-Val-Gly; [SEQ ID NO: 6] vii) Pro-Val-Gly-Val-Gly; [SEQ IDNO: 7] viii) Pro-Val-Gly-Gly-Val; [SEQ ID NO: 8] ix)Pro-Val-Val-Gly-Gly; [SEQ ID NO: 9] x) Pro-Gly-Gly-Val-Val; [SEQ ID NO:10] xi) Pro-Gly-Val-Gly-Val; [SEQ ID NO: 11] xii) Pro-Gly-Val-Val-Gly;[SEQ ID NO: 12] xiii) Val-Gly-Pro-Val-Gly; [SEQ ID NO: 13] xiv)Val-Gly-Pro-Gly-Val; [SEQ ID NO: 14] xv) Val-Val-Pro-Gly-Gly; [SEQ IDNO: 15] xvi) Gly-Gly-Pro-Val-Val; [SEQ ID NO: 16] xvii)Gly-Val-Pro-Gly-Val; [SEQ ID NO: 17] xviii) Gly-Val-Pro-Val-Gly; [SEQ IDNO: 18] xix) Val-Gly-Val-Pro-Gly; [SEQ ID NO: 19] xx)Val-Gly-Gly-Pro-Val; [SEQ ID NO: 20] xxi) Val-Val-Gly-Pro-Gly; [SEQ IDNO: 21] xxii) Gly-Gly-Val-Pro-Val; [SEQ ID NO: 22] xxiii)Gly-Val-Gly-Pro-Val; [SEQ ID NO: 23] xxiv) Gly-Val-Val-Pro-Gly; [SEQ IDNO: 24] xxv) Val-Gly-Val-Gly-Pro; [SEQ ID NO: 25] xxvi)Val-Gly-Gly-Val-Pro; [SEQ ID NO: 26] xxvii) Val-Val-Gly-Gly-Pro; [SEQ IDNO: 27] xxviii) Gly-Gly-Val-Val-Pro; [SEQ ID NO: 28] xxix)Gly-Val-Gly-Val-Pro; [SEQ ID NO: 29] and xxx) Gly-Val-Val-Gly-Pro. [SEQID NO: 30]

In another embodiment, the ECM mimetic peptide (Mim) may comprise somenumber of amino acids other than 5 such as 3 amino acids, 4 amino acids,6 amino acids, 7 amino acids, and so on. Non-limiting examples include:

i) Val-Pro-Gly-Gly [SEQ ID NO: 80] and ii) Ala-Pro-Gly-Val-Gly-Val. [SEQID NO: 81]

The disclosed ECM-mimetic peptides, Mim, and polymers of Mim (i.e.,polypeptide):

-[Mim]_(x)-

can be made through peptide (chemical) synthetic routes or throughmicrobial synthetic routes or combinations thereof. For example,poly(GVGVP) can be obtained by microbial synthesis. The gene containingthe sequence for either [Mim] or for the polymer of Mim, −[Mim]_(x)-,(or poly(GVGVP) protein) has been cloned and expressed in recombinant E.coli host system. After the desired batch of the fermentation, thepoly(GVGVP) can be purified from the E. coli lysate.

Biodegradable Moieties

The disclosed biocompatible polymers can comprise one or morebiodegradable moieties (identified as “BioDeg” in the formulae herein),wherein the biodegradable moieties do not comprise an amino acid. Afirst category of biodegradable moieties comprises monomers orhomopolymers of hydroxy acids such as lactide, glycolide, valerolactone,hydroxybutyrate, caprolactone, or mixtures thereof. Non-limitingexamples of biodegradable moieties, BioDeg, include:

i) Lactic acid;

ii) Glycolic acid;

iii) Lactide (di-lactic acid);

iv) Glycolide (di-glycolic acid);

v) Caprolactone;

vi) hydroxybutyrate;

vii) valerolactone;

viii) a hydroxy acid;

ix) a hydroxy fatty acid;

x) poly(lactide);

xi) poly(glycolide);

xii) poly(caprolactone);

xiii) poly(valerolactone);

xiv) poly(hydroxybutyrate);

xv) poly(lactide-co-glycolide);

xvi) poly(lactide-co-caprolactone);

xvii) poly(lactide-co-valerolactone);

xviii) poly(glycolide-co-caprolactone);

xix) poly(glycolide-co-valerolactone);

xx) poly(lactide-co-glycolide-co-caprolactone); and

xxi) poly(lactide-co-glycolide-co-valerolactone).

The biodegradable moieties, BioDeg, can be bonded directly to theECM-mimetic peptide (Mim) or can be bonded to the ECM-mimetic peptide(Mim) by a separate bond or linking unit, L, defined herein further.

A first embodiment of this category comprises homopolymers of lactide.This embodiment comprises from 1 to 100 residues of lactide and as suchcan be represented by the formula:

wherein the index y is from is from 0 to 100. In one iteration, theindex y is from 1 to 6.In another iteration, the index y is from 2 to 5. In a furtheriteration, the index y is from 8 to 12. In a yet further iteration, theindex y is from 9 to 11. In yet another iteration, the index y is from10 to 50. In a still further iteration, the index y is from 5 to 15. Ina yet still further iteration, the index y is from 20 to 40. However,the homopolymer can comprise any number of monomer units, for example,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and20. Non limiting examples include:

Another embodiment of this category comprises homopolymers of glycolide.This embodiment comprises from 1 to 100 residues of glycolide and assuch can be represented by the formula:

wherein the index y is from is from 0 to 100. In one iteration, theindex y is from 1 to 6.In another iteration, the index y is from 2 to 5. In a furtheriteration, the index y is from 8 to 12. In a yet further iteration, theindex y is from 9 to 11. In yet another iteration, the index y is from10 to 50. In a still further iteration, the index y is from 5 to 15. Ina yet still further iteration, the index y is from 20 to 40. However,the homopolymer can comprise any number of monomer units, for example,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and20. Non limiting examples include:

Another embodiment of this category comprises homopolymers ofcaprolactone. This embodiment comprises from 1 to 100 residues of6-hydroxyhexanoate and as such can be represented by the formula:

wherein the index y is from is from 0 to 100. In one iteration, theindex y is from 1 to 6.In another iteration, the index y is from 2 to 5. In a furtheriteration, the index y is from 8 to 12. In a yet further iteration, theindex y is from 9 to 11. In yet another iteration, the index y is from10 to 50. In a still further iteration, the index y is from 5 to 15. Ina yet still further iteration, the index y is from 20 to 40. However,the homopolymer can comprise any number of monomer units, for example,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and20. Non limiting examples include:

Linking Groups

The disclosed biocompatible polymers can further comprise one or morelinking groups. The linking groups, L, can serve to connect anECM-mimetic peptide (Mim) to a biodegradable moiety (BioDeg), forexample, polymers having the formula:

Also the linking groups can serve to connect blocks of ECM-mimeticpeptide and biodegradable moieties to other blocks of ECM-mimeticpeptide and biodegradable moieties, for example, polymers having theformula:

Further the linking groups can serve to both connect a ECM-mimeticpeptide to a biodegradable moiety and connect blocks of ECM-mimeticpeptides linked to biodegradable moieties to other blocks of ECM-mimeticpeptide and biodegradable moieties, for example, polymers having theformula:

Still further the linking groups can serve to both connect a ECM-mimeticpeptide to a biodegradable moiety and connect blocks of ECM-mimeticpeptides linked to biodegradable moieties to other blocks of ECM-mimeticpeptide and biodegradable moieties, for example, polymers having theformula:

Linking group L can be biodegradable or non-biodegradable. Non-limitingexamples of the disclosed linking groups can comprise one or more groupsor chemical bonds chosen from:

i) an alkyl;

ii) an alkoxy;

iii) a carbonyl;

iv) a halogen comprising leaving group;

v) an ester;

vi) an orthoester;

vii) an anhydride;

viii) a phosphate;

ix) a phosphazene;

x) a phosphoester;

xi) a dioxanaone;

xii) a carbonate;

xiii) an orthocarbonate;

xiv) an amide;

xv) an amine;

xvi) an ester amide;

xvii) a isocyanate;

xviii) a urethane;

xix) an etherester;

xx) a pyrrolidone;

xxi) or a unit comprising a combination of units (i) to (xx).

In one embodiment, the linking group is formed by a linking reagent thatcomprises at least one halogen leaving group. For example, a reactivemoiety having the formula:

X—(CH₂)_(t)—CO₂H;X—(CH₂)_(t)—CO₂CH₃; or X—(CH₂)_(t)—COCl

wherein X is a halogen leaving group and the index t is an integer from1 to 10. When fully incorporated into the disclosed polymer, reactivemoieties of this type can form linking groups having the formula:

In another embodiment, the linking group can itself be branched or canbe multi-functional so as to introduce branching the potential forperforming chemical crosslinking to the resulting polymer. For example,a linking group derived from an acid capable of forming a crosslink,inter alia, aspartic acid, glutamic acid, and citric acid. Or thecrosslinking unit can be derived from an amino acid, for example,lysine, ornithine, and the like.

In another embodiment, the linking group is formed by a linking reagentthat comprises two carbonyl reactive moieties. For example, a reactivemoiety having the formula:

HO₂C—(CH₂)_(t)—CO₂H;H₃CO₂C—(CH₂)_(t)—CO₂CH₃;ClOC—(CH₂)_(t)—COCl

wherein the index t is an integer from 1 to 10. When fully incorporatedinto the disclosed polymer, reactive moieties of this type can formlinking groups having the formula:

In further embodiment, the linking group is formed by a linking reagentthat comprises at least one halogen leaving group. For example, areactive moiety having the formula:

O═C═N—(CH₂)_(t)—N═C═O

wherein the index t is an integer from 1 to 10. When fully incorporatedinto the disclosed polymer, reactive moieties of this type can formlinking groups having the formula:

Further embodiments include linking groups having the formulae:

wherein for each the index t is an integer from 1 to 10.

The disclosed polymers can comprise a mixture of linking groups. Forexample, disclosed polymers having the formula:

can have a first linking group connecting the one or more ECM-mimeticpeptides to the one or more biodegradable moieties thereby forming ablock, and a second linking group connecting the plurality of blocks.

Specific Examples

One category of the disclosed polymers relates to biocompatible polymershaving the formula:

wherein R¹, R², R³, and R⁴ are each independently chosen from:

i) hydrogen;

ii) —CH₃;

iii) —CH₂CH₃;

iv) —CH₂CH₂CH₃;

v) —CH(CH₃)₂;

vi) —CH(CH₃)CH₂CH₃; and

vii) —CH₂CH₂CH(CH₃)₂;

the index w is an integer from 0 to 9; the index x is an integer from 1to 30; and the index z is an integer from 1 to 2000.

One embodiment relates to biocompatible polymers having the formula:

Non-limiting examples of this embodiment include:

Another embodiment relates to biocompatible polymers having the formula:

wherein R¹, R², R³, and R⁴ are each independently chosen from:

i) hydrogen;

ii) —CH₃;

iii) —CH₂CH₃;

iv) —CH₂CH₂CH₃;

v) —CH(CH₃)₂;

vi) —CH(CH₃)CH₂CH₃; and

vii) —CH₂CH₂CH(CH₃)₂;

the index w is an integer from 0 to 9; the index x is an integer from 1to 30; and the index z is an integer from 1 to 2000.

One embodiment relates to biocompatible polymers having the formula:

Non-limiting examples of this embodiment include:

Further embodiments include disclosed polymers having the formulae:

wherein R¹, R², R³, and R⁴ are each independently chosen from:

i) hydrogen;

ii) —CH₃;

iii) —CH₂CH₃;

iv) —CH₂CH₂CH₃;

v) —CH(CH₃)₂;

vi) —CH(CH₃)CH₂CH₃; and

vii) —CH₂CH₂CH(CH₃)₂;

the index w is an integer from 0 to 9; the index x is an integer from 1to 30; and the index z is an integer from 1 to 2000.

Uses

The disclosed polymers can be used in a variety of medical,pharmaceutical, medical device, veterinarian applications. Generally,non-limiting examples of applications for the disclosed polymers includethe use of these polymers:

-   -   (a) As devices including stents, implants, medical devices,        medical products and the like including, without being limiting,        examples such as stents, implants, films, foams, sponges,        patches, matrices, fabrics, meshes, membranes, felts, solids,        liquids, viscous liquids, viscoelastic materials, gels,        hydrogels, and so on.    -   (b) As coatings on: stents, implants, devices, medical devices,        medical products, and so on.    -   (c) For delivery or administration of bioactive agents or other        medically useful agents including: contrast agents, imaging        agents, bioactive agents, drugs, small molecule drugs, peptides,        proteins, nucleic acids, antibodies, antibody fragments,        factors, aptamers, and so on.    -   (d) As drug-eluting polymer coatings or films on devices        including stents, implants, medical devices, medical products,        and so on.

These polymers can be used for delivery or administration of bioactiveagents or other medically useful agents from various forms includingnon-limiting examples such as films, sheets, coatings, particles,microparticles, nanoparticles, capsules, microcapsules, nanocapsules,implants, foams, sponges, patches, matrices, fabrics, meshes, membranes,felts, solids, liquids, viscous liquids, viscoelastic materials, gels,hydrogels, and so on.

The following are non-limiting examples of bioactive agents that canadministered using the polymers of the present invention and hereininclude, but are not limited to, peptides, proteins such as hormones,enzymes, antibodies, monoclonal antibodies, antibody fragments,monoclonal antibody fragments, and the like, nucleic acids such asaptamers, siRNA, DNA, RNA, antisense nucleic acids or the like,antisense nucleic acid analogs or the like, low-molecular weightcompounds, or high-molecular-weight compounds, receptor agonists,receptor antagonists, partial receptor agonists, and partial receptorantagonists.

Representative drugs or bioactive agents that can be used in themicroparticle composition of the present disclosure include, but are notlimited to, peptide drugs, protein drugs, desensitizing materials,antigens, factors, growth factors, anti-infective agents such asantibiotics, antimicrobial agents, antiviral, antibacterial,antiparasitic, antifungal substances and combination thereof,antiallergenics, steroids, androgenic steroids, decongestants,hypnotics, steroidal anti-inflammatory agents, anti-cholinergics,sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers,vaccines, estrogens, progestational agents, humoral agents,prostaglandins, analgesics, antispasmodics, antimalarials,antihistamines, cardioactive agents, nonsteroidal anti-inflammatoryagents, antiparkinsonian agents, anti-Alzheimer's agents,antihypertensive agents, beta-adrenergic blocking agents,alpha-adrenergic blocking agents, nutritional agents, and thebenzophenanthridine alkaloids. The bioactive agent can further be asubstance capable of acting as a stimulant, a sedative, a hypnotic, ananalgesic, an anticonvulsant, and the like.

Further, polymers disclosed herein can be used to deliver or administerCNS-active drugs, neuro-active drugs, inflammatory and anti-inflammatorydrugs, renal and cardiovascular drugs, gastrointestinal drugs,anti-neoplastics, immunomodulators, immunosuppressants, hematopoieticagents, growth factors, anticoagulant, thrombolytic, antiplateletagents, hormones, hormone-active agents, hormone antagonists, vitamins,ophthalmic agents, anabolic agents, antacids, anti-asthmatic agents,anti-cholesterolemic and anti-lipid agents, anti-convulsants,anti-diarrheals, anti-emetics, anti-manic agents, antimetabolite agents,anti-nauseants, anti-obesity agents, anti-pyretic and analgesic agents,anti-spasmodic agents, anti-thrombotic agents, anti-tussive agents,anti-uricemic agents, anti-anginal agents, antihistamines, appetitesuppressants, biologicals, cerebral dilators, coronary dilators,bronchiodilators, cytotoxic agents, decongestants, diuretics, diagnosticagents, erythropoietic agents, expectorants, gastrointestinal sedatives,hyperglycemic agents, hypnotics, hypoglycemic agents, laxatives, mineralsupplements, mucolytic agents, neuromuscular drugs, peripheralvasodilators, psychotropics, stimulants, thyroid and anti-thyroidagents, tissue growth agents, uterine relaxants, vitamins, antigenicmaterials, and so on. Other classes of bioactive agents include thosecited in Goodman & Gilman's The Pharmacological Basis of Therapeutics(McGraw Hill) as well as bioactive agents included in the Merck Indexand The Physicians Desk Reference (Thompson Healthcare).

Other bioactive agents include androgen inhibitors, polysaccharides,growth factors (e.g., a vascular endothelial growth factor-VEGF),hormones, anti-angiogenesis factors, dextromethorphan, dextromethorphanhydrobromide, noscapine, carbetapentane citrate, chlophedianolhydrochloride, chlorpheniramine maleate, phenindamine tartrate,pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate,phenylephrine hydrochloride, phenylpropanolamine hydrochloride,pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeinesulfate morphine, mineral supplements, cholestryramine,N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide,magnesium hydroxide, peptides, polypeptides, proteins, amino acids,hormones, interferons, cytokines, and vaccines.

Further examples of bioactive agents include, but are not limited to,peptide drugs, protein drugs, desensitizing materials, antigens,anti-infective agents such as antibiotics, antimicrobial agents,antiviral, antibacterial, antiparasitic, antifungal substances andcombination thereof, antiallergenics, androgenic steroids,decongestants, hypnotics, steroidal anti-inflammatory agents,anti-cholinergics, sympathomimetics, sedatives, miotics, psychicenergizers, tranquilizers, vaccines, estrogens, progestational agents,humoral agents, prostaglandins, analgesics, antispasmodics,antimalarials, antihistamines, antiproliferatives, anti-VEGF agents,cardioactive agents, nonsteroidal anti-inflammatory agents,antiparkinsonian agents, antihypertensive agents, β-adrenergic blockingagents, nutritional agents, and the benzophenanthridine alkaloids. Theagent can further be a substance capable of acting as a stimulant,sedative, hypnotic, analgesic, anticonvulsant, and the like.

The controlled release system can comprise a large number of bioactiveagents either singly or in combination. Other bioactive agents includebut are not limited to analgesics such as acetaminophen, acetylsalicylicacid, and the like; anesthetics such as lidocaine, xylocalne, and thelike; anorexics such as dexadrine, phendimetrazine tartrate, and thelike; antiarthritics such as methylprednisolone, ibuprofen, and thelike; antiasthmatics such as terbutaline sulfate, theophylline,ephedrine, and the like; antibiotics such as sulfisoxazole, penicillinG, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines,chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and thelike; antifungals such as amphotericin B, nystatin, ketoconazole, andthe like; antivirals such as acyclovir, amantadine, and the like;anticancer agents such as cyclophosphamide, methotrexate, etretinate,paclitaxel, taxol, and the like; anticoagulants such as heparin,warfarin, and the like; anticonvulsants such as phenyloin sodium,diazepam, and the like; antidepressants such as isocarboxazid,amoxapine, and the like; antihistamines such as diphenhydramine HCl,chlorpheniramine maleate, and the like; hormones such as insulin,progestins, estrogens, corticoids, glucocorticoids, androgens, and thelike; tranquilizers such as thorazine, diazepam, chlorpromazine HCl,reserpine, chlordiazepoxide HCl, and the like; antispasmodics such asbelladonna alkaloids, dicyclomine hydrochloride, and the like; vitaminsand minerals such as essential amino acids, calcium, iron, potassium,zinc, vitamin B₁₂, and the like; cardiovascular agents such as prazosinHCl, nitroglycerin, propranolol HCl, hydralazine HCl, pancrelipase,succinic acid dehydrogenase, and the like; peptides and proteins such asLHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptides,growth releasing factor, angiotensin, FSH, EGF, bone morphogenic protein(BMP), erythopoeitin (EPO), interferon, interleukin, collagen,fibrinogen, insulin, Factor VIII, Factor IX, Enbrel®, Rituxam®,Herceptin®, alpha-glucosidase, Cerazyme/Ceredose®, vasopressin, ACTH,human serum albumin, gamma globulin, structural proteins, blood productproteins, complex proteins, enzymes, antibodies, monoclonal antibodies,and the like; prostaglandins; nucleic acids; carbohydrates; fats;narcotics such as morphine, codeine, and the like, psychotherapeutics;anti-malarials, L-dopa, diuretics such as furosemide, spironolactone,and the like; antiulcer drugs such as rantidine HCl, cimetidine HCl, andthe like.

The bioactive agent can also be an immunomodulator, including, forexample, cytokines, interleukins, interferon, colony stimulating factor,tumor necrosis factor, and the like; immunosuppressants such asrapamycin, tacrolimus, and the like; allergens such as cat dander, birchpollen, house dust mite, grass pollen, and the like; antigens ofbacterial organisms such as Streptococcus pneumoniae, Haemophilusinfluenzae, Staphylococcus aureus, Streptococcus pyrogenes,Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis,Clostridium tetani, Clostridium botulinum, Clostridium perfringens.Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans.Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae,Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibriocholerae, Legionella pneumophila, Mycobacterium tuberculosis,Mycobacterium leprae, Treponema pallidum, Leptspirosis interrogans,Borrelia burgddorferi, Campylobacter jejuni, and the like; antigens ofsuch viruses as smallpox, influenza A and B, respiratory synctial,parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus,papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses,equine encephalitis, Japanese encephalitis, yellow fever, Rift Valleyfever, lymphocytic choriomeningitis, hepatitis B, and the like; antigensof such fungal, protozoan, and parasitic organisms such as Cryptococcucneoformans, Histoplasma capsulatum, Candida albicans, Candidatropicalis, Nocardia asteroids, Rickettsia ricketsii, Rickettsia typhi,Mycoplasma pneumoniae, Chlamyda psittaci, Chlamydia trachomatis,Plasmodium falciparum, Trypanasoma brucei, Entamoeba histolytica,Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni, and thelike. These antigens may be in the form of whole killed organisms,peptides, proteins, glycoproteins, carbohydrates, or combinationsthereof.

In a further specific aspect, the bioactive agent comprises anantibiotic. The antibiotic can be, for example, one or more of Amikacin,Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin,Paromomycin, Ansamycins, Geldanamycin, Herbimycin, Carbacephem,Loracarbef, Carbapenems, Ertapenem, Doripenem, Imipenem/Cilastatin,Meropenem, Cephalosporins (First generation), Cefadroxil, Cefazolin,Cefalotin or Cefalothin, Cefalexin, Cephalosporins (Second generation),Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cephalosporins(Third generation), Cefixime, Cefdinir, Cefditoren, Cefoperazone,Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime,Ceftriaxone, Cephalosporins (Fourth generation), Cefepime,Cephalosporins (Fifth generation), Ceftobiprole, Glycopeptides,Teicoplanin, Vancomycin, Macrolides, Azithromycin, Clarithromycin,Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin,Telithromycin, Spectinomycin, Monobactams, Aztreonam, Penicillins,Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin,Dicloxacillin, Flucloxacillin, Mezlocillin, Meticillin, Nafcillin,Oxacillin, Penicillin, Piperacillin, Ticarcillin, Polypeptides,Bacitracin, Colistin, Polymyxin B, Quinolones, Ciprofloxacin, Enoxacin,Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin,Ofloxacin, Trovafloxacin, Sulfonamides, Mafenide, Prontosil (archaic),Sulfacetamide, Sulfamethizole, Sulfanilimide (archaic), Sulfasalazine,Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfamethoxazole(Co-trimoxazole) (TMP-SMX), Tetracyclines, including Demeclocycline,Doxycycline, Minocycline, Oxytetracycline, Tetracycline, and others;Arsphenamine, Chloramphenicol, Clindamycin, Lincomycin, Ethambutol,Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid,Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide,Quinupristin/Dalfopristin, Rifampicin (Rifampin in U.S.), Timidazole, ora combination thereof. In one aspect, the bioactive agent can be acombination of Rifampicin (Rifampin in U.S.) and Minocycline.

When the disclosed polymers are used to prepare vascular grafts they canhave similar characteristics to native vessels while at the same timeeliciting a desired biological response, for example, elastin mimeticresponse. The biocompatible polymers disclosed herein can be used in oneor more ways or configurations. In one embodiment, synthetic vasculargrafts comprising the disclosed biocompatible polymers can be preparedin varying sizes or lengths using techniques known to those of ordinaryskill in the art. For example, fabrication of these synthetic vesselscan be achieved using an electrospinning apparatus to shape and form thevascular graft to the desired diameter, thickness, and length. In someiterations the biocompatible polymers can comprise crosslinkable unitsso that the polymer can be further crosslinked to provide the desiredmechanical rigidity, for example, when fabrication arterial grafts.

In another embodiment, natural vascular grafts can be coated with one ormore of the disclosed biocompatible polymers. In this embodiment, thepolymer coating elicits a biological response that aids in the body'sability to assimilate the graft. Also, the use of ECM-mimetic peptidecontaining polymers allows for more rapid healing, for example, in thecase wherein a mixture of elastin and fibrinogen-mimetic peptides areused.

Further disclosed herein are biomechanical devices that comprise one ormore of the biocompatible polymers. For example, stents used inovercoming arterial blockage can be coated with the disclosed polymersin order to elicit one or more desirable responses. These responses caninclude wound healing or enhancement of arterial wall integrity.

Another embodiment of biomechanical devices relates to joint replacementtherapy, for example, hip and knee replacement apparatus. Otherbiomechanical devices include sutures, for example, arterial sutures.The sutures can comprise the disclosed polymers or standardbiocompatible sutures can be coated with the disclosed polymers.

The disclosed biocompatible polymers can be used to form films ormembranes. For example, they can be used for tissue regenerationapplications when the polymer is fashioned into a membrane or film andused as a patch for tissue reconstruction (e.g., cardiac or bladdertissue reconstruction), skin graft, and the like.

The disclosed biocompatible polymers can also be used a coatings on amedical device. A particularly desirable coating is a drug-elutingcoating on a device such as a stent. Alternatively, the disclosedbiodegradable polymer can be used to prepare a fully degradable polymerstent (with or without added drug; with or without a drug-elutingpolymer coating on top of the degradable polymer stent).

Preparations

The present disclosure further relates to method for preparing thedisclosed biocompatible polymers.

Step (a)

Step (a) comprises providing an ECM-mimetic peptide-comprising reagenthaving the formula:

HN-Xaa-Xbb-Xcc-Xdd-Xee-OH

wherein Xaa, Xbb, Xcc, Xdd, and Xee, are each independently an aminoacid residue.

A non-limiting example of an ECM-mimetic peptide-comprising reagent isvalinylprolinylglycinylvalinylglycine having the formula:

i) Val-Pro-Gly-Gly-Val; [SEQ ID NO: 2] ii) Val-Pro-Val-Gly-Gly; [SEQ IDNO: 3] iii) Gly-Pro-Gly-Val-Val; [SEQ ID NO: 4] iv) Gly-Pro-Val-Gly-Val;[SEQ ID NO: 5] v) Gly-Pro-Val-Val-Gly; [SEQ ID NO: 6] vi)Pro-Val-Gly-Val-Gly; [SEQ ID NO: 7] vii) Pro-Val-Gly-Gly-Val; [SEQ IDNO: 8] viii) Pro-Val-Val-Gly-Gly; [SEQ ID NO: 9] ix)Pro-Gly-Gly-Val-Val; [SEQ ID NO: 10] x) Pro-Gly-Val-Gly-Val; [SEQ ID NO:11] xi) Pro-Gly-Val-Val-Gly; [SEQ ID NO: 12] xii) Val-Gly-Pro-Val-Gly;[SEQ ID NO: 13] xiii) Val-Gly-Pro-Gly-Val; [SEQ ID NO: 14] xiv)Val-Val-Pro-Gly-Gly; [SEQ ID NO: 15] xv) Gly-Gly-Pro-Val-Val; [SEQ IDNO: 16] xvi) Gly-Val-Pro-Gly-Val; [SEQ ID NO: 17] xvii)Gly-Val-Pro-Val-Gly; [SEQ ID NO: 18] xviii) Val-Gly-Val-Pro-Gly; [SEQ IDNO: 19] xix) Val-Gly-Gly-Pro-Val; [SEQ ID NO: 20] xx)Val-Val-Gly-Pro-Gly; [SEQ ID NO: 21] xxi) Gly-Gly-Val-Pro-Val; [SEQ IDNO: 22] xxii) Gly-Val-Gly-Pro-Val; [SEQ ID NO: 23] xxiii)Gly-Val-Val-Pro-Gly; [SEQ ID NO: 24] xxiv) Val-Gly-Val-Gly-Pro; [SEQ IDNO: 25] xxv) Val-Gly-Gly-Val-Pro; [SEQ ID NO: 26] xxvi)Val-Val-Gly-Gly-Pro; [SEQ ID NO: 27] xxvii) Gly-Gly-Val-Val-Pro; [SEQ IDNO: 28] xxviii) Gly-Val-Gly-Val-Pro; [SEQ ID NO: 29] and xxix)Gly-Val-Val-Gly-Pro. [SEQ ID NO: 30]

In one iteration, Step (a) comprises providing an ECM-mimeticpeptide-comprising reagent having the formula:

HN-(Xaa-Xbb-Xcc-Xdd-Xee)x-OH

wherein Xaa, Xbb, Xcc, Xdd, and Xee are each independently an amino acidresidue, and the index x is an integer from 1 to 100.

A non-limiting example of an ECM-mimetic peptide comprising reagentaccording to this iteration wherein x is equal to 2 has the formula:

The ECM mimetic peptide, Mim, or the polypeptide (Mim)_(x), can beprepared by known chemical synthesis methods. Preferably, however, thepolypeptide (Mim)_(x) is prepared through known microbial syntheticmethods.

Step (b)

Step (b) comprises providing a biodegradable reagent such as aprepolymer that does not comprise an α-amino acid. In one embodiment,the biodegradable reagent can be a homopolymer, copolymer, or blockcopolymer of a non-α-amino acid comprising monomer. Non-limitingexamples include:

i) poly(lactide);

ii) poly(glycolide);

iii) poly(caprolactone);

iv) poly(valerolactone);

v) poly(lactide-co-glycolide);

vi) poly(lactide-co-caprolactone);

vii) poly(lactide-co-valerolactone);

viii) poly(glycolide-co-caprolactone);

ix) poly(glycolide-co-valerolactone);

x) poly(lactide-co-glycolide-co-caprolactone); and

xi) poly(lactide-co-glycolide-co-valerolactone).

In a further embodiment, the biodegradable reagent can comprise a singlemonomeric unit, for example, lactic acid, glycolic acid,6-hydroxyhexanoic acid, a hydroxy acid, a hydroxy acid fatty acid, andthe like, or a reagent that results in the inclusion of a singlemonomeric unit that incorporates a biodegradable functionality into thepolymer backbone. Still further the biodegradable reagent can comprisedimers or trimers of lactic acid and so forth. These reagents can beprepared by methods known in the art or, in some cases, are commerciallyavailable.

Step (c)

Step (c) comprises contacting the ECM-mimetic peptide-comprising reagentfrom step (a) with the biodegradable reagent from step (b) to form acombination of (Mim)_(x)-(BioDeg)_(y). In a further embodiment of step(c), the step involves contacting the ECM-mimetic peptide-comprisingreagent from either step (a) or the biodegradable reagent from step (b)with a linking reagent, wherein the linking reagent introduces one ormore linking groups or bonds between the ECM-mimetic peptide-comprisingreagent and the biodegradable reagent including moieties chosen from:

i) an alkyl;

ii) an alkoxy;

iii) a carbonyl;

iv) a halogen comprising leaving group;

v) an ester;

vi) an orthoester;

vii) an anhydride;

viii) a phosphate;

ix) a phosphazene;

x) a phosphoester;

xi) a dioxanaone;

xii) a carbonate;

xiii) an orthocarbonate;

xiv) an amide;

xv) an amine;

xvi) an ester amide;

xvii) a isocyanate;

xviii) a urethane;

xix) an etherester;

xx) a pyrrolidone; or

xxi) a unit comprising a combination of units (i) to (xx).

The resulting combination of (Mim)_(x)-(BioDeg)_(y) can be terminated onone end with either an —NH₂ or an —OH group and on the other end by a—COOH group. This facilitates the polymerization in the next step, step(d).

Step (d)

Step (d) involves the polymerization of the (Mim)_(x)-(BioDeg)_(y)entity formed in step (c). The polymerization reaction can be performedwith various synthetic techniques. One method includes apolycondensation reaction where (Mim)_(x)-(BioDeg)_(y), having either anamine or hydroxyl group on one end and a carboxylic acid group on theother end, reacts. A second method includes the use of peptide couplingreagents to link together amine or hydroxyl end-groups with thecarboxylic acid groups. This approach is the one shown Step 3 of thescheme below where EDC is the peptide coupling agent. EDC firstactivates the carboxylic acid group, which then becomes a reactive sitefor the hydroxyl end-groups to attack. Successive reactions then areused to form the final biodegradable ECM-mimetic polymer. Thus, theresult of step (d) can be described as -(-(Mim)_(x)-(BioDeg)_(y))_(z),where indicia x, y, and z are as defined herein.

In a further embodiment, linking groups, L, can be incorporated into thepolymer in various ways. For example, the chemistries described in steps(c) or (d), or both, can involve reactive reagents that are useful incoupling together Mim_(x) and BioDeg_(y) (step c) and in preparing thepolymer (step d). Such coupling steps can introduce linking groups orbonds to the composition (linking groups “L”). Some reactive reagentsuseful for performing these coupling steps could include carboxylic acidactivating reagents such as: NHS, IIDQ, EDCI, CDI, HOBt, DCCI (forexamples, see Principles of Peptide Synthesis, M. Bodanszky,Springer-Verlag, 1984; Amino Acid and Peptide Synthesis (2^(nd)Edition), John Jones, Oxford University Press, 2002), which are oftenuseful in preparing amide bonds through the coupling of carboxylic acidswith amine groups and in preparing ester bonds through the coupling ofcarboxylic acids with hydroxyl groups.

Throughout the specification and claims ECM-mimetics are represented invarious ways, however, when possible short-hand notation is used, forexample, for the 5-amino acid comprising ECM-mimeticvalylprolylglycylvalylglycine [SEQ ID NO: 1], the short hand notationVPGVG [SEQ ID NO: 1] is used. When describing chemical synthesis of thedisclosed polymers alternative representations are used, however, theartisan will know that these representations are used to facilitate theunderstanding of chemical reactions which can take place at the terminalamino and carboxy terminus of an ECM-mimetic. For example, the formulaH₂N-[VPGVG]-CO₂H [SEQ ID NO: 1] stands equally well for VPGVG [SEQ IDNO:1].

EXAMPLES

The following examples are set forth below to illustrate the methods andresults according to the disclosed subject matter. These examples arenot intended to be inclusive of all aspects of the subject matterdisclosed herein, but rather to illustrate representative methods andresults. These examples are not intended to exclude equivalents andvariations of the present invention which are apparent to one skilled inthe art.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, pH, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric. There are numerous variations and combinations ofconditions, e.g., component concentrations, temperatures, pressures, andother reaction ranges and conditions that can be used to optimize theproduct purity and yield obtained from the described process. Onlyreasonable and routine experimentation will be required to optimize suchprocess conditions.

Prophetic Example 1 Synthesis of an ECM-Mimetic Peptide

Scheme I outlines the preparation of the ECM-mimetic peptide VPGVG [SEQID NO:1].

The pentapeptide H₂N-[VPGVG]-CO₂H can be prepared by other similarsynthetic procedures, for example, using standard coupling procedures orusing polymer supported (Merrifield) coupling procedures. In otherexamples, microbial fermentation can be used to prepare the pentapeptide(as well as the polypentapeptide). The following is a non-limitingprophetic example of the preparation of VPGVG [SEQ ID NO:1].

Step (i)

Preparation of N-Cbz-valylproline methyl ester (Cbz-NH-[VP]-CO₂CH₃): Toa solution of N-Cbz-valine (2.5 g, 10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) andtriethylamine (2.0 g, 20 mmol) in DMF (10 mL) is added dropwise asolution of proline methyl ester hydrochloride (1.8 g, 11 mmol) in DMF(5 mL). The solution is stirred at room temperature and the reactionmonitored by TLC until the disappearance of N-Cbz-valine. The reactionsolution is then diluted with dichloromethane (30 mL) and the organiclayer is extracted with 0.1 N HCl (20 mL), water (20 mL), then driedover Na₂SO₄. The solvent is removed in vacuo to afford the desiredcompound.

Step (ii)

Preparation of N-Cbz-valylproline (Cbz-NH-[VP]-CO₂H): To a solution ofN-Cbz-valylproline methyl ester (Cbz-NH-[VP]-CO₂CH₃) (3.62 g, 10 mmol)in THF (10 mL) is added a 1M aqueous solution of LiOH (11 mL, 11 mmol)and the solution is stirred overnight. The resulting solution isacidified to pH about 7 with 1M HCl and the contents of the flaskpartitioned between water (20 mL) and ethyl acetate (20 mL). The organicphase is extracted with brine, dried over Na₂SO₄ then concentrated invacuo to afford the desired compound.

Step (iii)

Preparation of N-Cbz-valylprolylglycine methyl ester(Cbz-NH-[VPG]-CO₂CH₃): To a solution of N-Cbz-valylproline(Cbz-NH-[VP]-CO₂H) (3.5 g, 10 mmol),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) andtriethylamine (2.0 g, 20 mmol) in DMF (15 mL) is added dropwise asolution of glycine methyl ester hydrochloride (1.38 g, 11 mmol) in DMF(5 mL). The solution is stirred at room temperature and the reactionmonitored by TLC until the disappearance of N-Cbz-valylproline. Thereaction solution is then diluted with dichloromethane (50 mL) and theorganic layer is extracted with 0.1 N HCl (20 mL), water (20 mL), thendried over Na₂SO₄. The solvent is removed in vacuo to afford the desiredcompound.

Step (iv)

Preparation of N-Cbz-valylprolylglycine (Cbz-NH-[VPG]-CO₂H): To asolution of N-Cbz-valylprolylglycine methyl ester (Cbz-NH-[VPG]-CO₂CH₃)(4.2 g, 10 mmol) in THF (20 mL) is added a 1M aqueous solution of LiOH(11 mL, 11 mmol) and the solution is stirred overnight. The resultingsolution is acidified to pH about 7 with 1M HCl and the contents of theflask partitioned between water (30 mL) and ethyl acetate (30 mL). Theorganic phase is extracted with brine, dried over Na₂SO₄ thenconcentrated in vacuo to afford the desired compound.

Step (v)

Preparation of N-Cbz-valylprolylglycylvaline methyl ester(Cbz-NH-[VPGV]-CO₂CH₃): To a solution of N-Cbz-valylprolylglycine(Cbz-NH-[VPG]-CO₂H) (4.05 g, 10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) andtriethylamine (2.0 g, 20 mmol) in DMF (15 mL) is added dropwise asolution of valine methyl ester hydrochloride (1.8 g, 11 mmol) in DMF (5mL). The solution is stirred at room temperature until the disappearanceof N-Cbz-valylprolylglycine. The reaction solution is then diluted withdichloromethane (50 Ml) and the organic layer is extracted with 0.1 NHCl (20 mL), water (20 mL), then dried over Na₂SO₄. The solvent isremoved in vacuo to afford the desired compound.

Step (vi)

Preparation of N-Cbz-valylprolylglycylvaline (Cbz-NH-[VPGV]-CO₂H): To asolution of N-Cbz-valylprolylglycylvaline methyl ester(Cbz-NH-[VPGV]-CO₂CH₃) (5.2 g, 10 mmol) in THF (25 mL) is added a 1Maqueous solution of LiOH (11 mL, 11 mmol) and the solution is stirredovernight. The resulting solution is acidified to pH about 7 with 1M HCland the contents of the flask partitioned between water (30 Ml) andethyl acetate (30 mL). The organic phase is extracted with brine, driedover Na₂SO₄ then concentrated in vacuo to afford the desired compound.

Step (vii)

Preparation of N-Cbz-valylprolylglycylvalylglycine methyl ester(Cbz-NH-[VPGVG]-CO₂CH₃): To a solution of N-Cbz-valylprolylglycylvaline(Cbz-NH-[VPGV]-CO₂H) (5.54 g, 10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) andtriethylamine (2.0 g, 20 mmol) in DMF (15 mL) is added dropwise asolution of glycine methyl ester hydrochloride (1.38 g, 11 mmol) in DMF(5 mL). The solution is stirred at room temperature until thedisappearance of N-Cbz-valylprolylglycylvaline. The reaction solution isthen diluted with dichloromethane (50 mL) and the organic layer isextracted with 0.1 N HCl (20 mL), water (20 mL), then dried over Na₂SO₄.The solvent is removed in vacuo to afford the desired compound.

Step (viii)

Preparation of N-Cbz-valylprolylglycylvalylglycine(Cbz-NH-[VPGVG]-CO₂H): To a solution ofN-Cbz-valylprolylglycylvalylglycine methyl ester(Cbz-NH-[VPGVG]-CO₂CH₃): (5.75 g, 10 mmol) in THF (30 mL) is added a 1Maqueous solution of LiOH (11 mL, 11 mmol) and the solution is stirredovernight. The resulting solution is acidified to pH about 7 with 1M HCland the contents of the flask partitioned between water (25 mL) andethyl acetate (50 mL). The organic phase is extracted with brine, driedover Na₂SO₄ then concentrated in vacuo to afford the desired compound.

Step (ix)

Preparation of valylprolylglycylvalylglycine (H₂N-[VPGVG]-CO₂H) [SEQ IDNO:1]: N-Cbz-valylprolylglycylvalylglycine (Cbz-NH-[VPGVG]-CO₂H) (5.5 g,10 mmol) in methanol (100 mL) is charged to a 500 mL Parr hydrogenationvessel. 10% Pd/C (10 mg) is added under nitrogen atmosphere. Thesolution is hydrogenated for 3 hours under 45 psi of hydrogen gas withsufficient shaking to insure complete dispersion of the catalyst. Thenitrogen purged solution is then filtered through Celite™ to remove thecatalyst. The filtrate is concentrated in vacuo to afford the desiredproduct.

Prophetic Example 2 Synthesis of an ECM-Mimetic Peptide

Scheme II outlines the preparation of [VPGVG]₂ [SEQ ID NO:31] asdescribed in Example 2 herein below.

The pentapeptide H₂N-[VPGVG]₂—CO₂H [SEQ ID NO:31] can be prepared byother techniques. The following is a non-limiting prophetic example ofthe preparation of H₂N-[VPGVG]₂—CO₂H [SEQ ID NO:31].

Step (i)

Preparation of valylprolylglyclyvalylglycine methyl ester(H₂N-[VPGVG]-CO₂CH₃): N-Cbz-valylprolyl-glycylvalylglycine methyl ester(Cbz-NH-[VPGVG]-CO₂CH₃) (5.75 g, 10 mmol) in methanol (100 mL) ischarged to a 500 mL Parr hydrogenation vessel. 10% Pd/C (10 mg) is addedunder nitrogen blanketing. The solution is hydrogenated for 3 hoursunder 45 psi of hydrogen gas with sufficient shaking to insure completedispersion of the catalyst. The nitrogen purged solution is thenfiltered through Celite™ to remove the catalyst. The filtrate isconcentrated in vacuo to afford the desired product.

Step (ii)

Preparation ofN-Cbz-Valylprolylglycylvalylglycylvalylprolylglycylvalylglycine Methylester (Cbz-NH-[VPGVG]₂—CO₂CH₃): To a solution ofN-Cbz-valylprolylglycylvalylglycine (Cbz-NH-[VPGVG]-CO₂H) (5.6 g, 10mmol) [as prepared in step (h) of Scheme I herein above],1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) andtriethylamine (2.0 g, 20 mmol) in DMF (30 mL) is added dropwise asolution of valylprolylglycylvalyl-glycine methyl ester(H₂N-[VPGVG]-CO₂CH₃) (4.85 g, 11 mmol) in DMF (20 mL). The solution isstirred at room temperature and the reaction monitored by TLC until thedisappearance of N-Cbz-valylprolylglycylvalylglycine. The reactionsolution is then diluted with dichloromethane (50 mL) and the organiclayer is extracted with 0.1 N HCl (20 mL), water (20 mL), then driedover Na₂SO₄. The solvent is removed in vacuo to afford the desiredcompound.

Step (iii)

Preparation ofN-Cbz-Valylprolylglycylvalylglycylvalylprolylglycylvalylglycine(Cbz-NH-[VPGVG]₂-CO₂H): To a solution ofN-Cbz-valylprolylglycylvalylglycylvalyl-prolylglycylvalylglycine methylester (Cbz-NH-[VPGVG]₂-CO₂CH₃) (9.8 g, 10 mmol) in THF (50 mL) is addeda 1M aqueous solution of LiOH (11 mL, 11 mmol) and the solution isstirred overnight. The resulting solution is acidified to pH about 7with 1M HCl and the contents of the flask partitioned between water (50mL) and ethyl acetate (50 mL). The organic phase is extracted withbrine, dried over Na₂SO₄ then concentrated in vacuo to afford thedesired compound.

Step (iv)

Preparation of valylprolylglycylvalylglycylvalylprolylglycylvalylglycine[VPGVG]₂ (H₂N-[VPGVG]₂-CO₂H) [SEQ ID NO:31]: To a solution ofN-Cbz-valylprolylglycylvalyl-glycylvalylprolylglycylvalylglycine(Cbz-NH-[VPGVG]₂-CO₂H) (8.5 g, 10 mmol) in methanol (100 mL) is chargedto a 500 mL Parr hydrogenation vessel. 10% Pd/C (10 mg) is added. Thesolution is hydrogenated for 3 hours under 45 psi of hydrogen gas withsufficient shaking to insure complete dispersion of the catalyst. Thenitrogen purged solution is then filtered through Celite to remove thecatalyst. The filtrate is concentrated in vacuo to afford the desiredproduct.

Prophetic Example 3 Synthesis of an ECM-Mimetic Peptide

Scheme III outlines the preparation of [VPGVG]₅ [SEQ ID NO:82] using theprocedures as described in Example 2.

Prophetic Example 4 Synthesis of a Biocompatible Biodegradable Polymeras Disclosed Herein

Scheme IV outlines the preparation of a biodegradable elastomericpolymer [VPGVG]₅-lactate using Cbz-NH-[VPGVG]₅-CO₂H as the startingmaterial, which can be prepared as outlined in Scheme III using theprocedures outlined in Scheme II and described in Example 2.

Prophetic Example 5 Synthesis of a Biocompatible Biodegradable Polymeras Disclosed Herein

The following is a prophetic example of the synthesis of thebiocompatible biodegradable polymer H₂N-[VPGVG]₅-lactate.

Step (i)

Preparation of Cbz-NH-[VPGVG]₅-CO₂CH(CH₃)CO₂CH₃: To a solution ofN-Cbz-[VPGVG]₅-CO₂H (2.24 g, 1 mmol) in DMF (30 mL) is added1,1′-carbonyldiimidazole (0.32 g, 2 mmol). The reaction solution iscooled in an ice bath and a solution of methyl lactate (0.21 g, 2 mmol)in DMF (2 mL) is added. The reaction is followed by TLC until thedisappearance of the acid. The reaction solution is partitioned betweenwater and ethyl acetate/dichloromethane (3:1) (20 mL). The solution iswashed with additional water (10 mL aliquots) until the disappearance ofmethyl lactate. The organic phase is dried and concentrated to affordthe desired product.

Step (ii)

Preparation of Cbz-NH-[VPGVG]₅-CO₂CH(CH₃)CO₂H: To a solution ofCbz-NH-[VPGVG]₅-CO₂CH(CH₃)CO₂CH₃ (2.3 g, 1 mmol) in THF (30 mL) is addeda 1M aqueous solution of LiOH (1.1 mL, 1.1 mmol) and the solution isstirred overnight. The resulting solution is acidified to Ph about 7with 1M HCl and the contents of the flask partitioned between water (50Ml) and ethyl acetate (50 mL). The organic phase is extracted withbrine, dried over Na₂SO₄ then concentrated in vacuo to afford thedesired compound.

Step (iii)

Preparation of H₂N-[VPGVG]₅-CO₂CH(CH₃)CO₂H: To a solution ofCbz-NH-[VPGVG]₅-CO₂CH(CH₃)CO₂H (2.25 g, 1 mmol) in methanol (100 mL) ischarged to a 500 mL Parr hydrogenation vessel. 10% Pd/C (10 mg) isadded. The solution is hydrogenated for 3 hours under 45 psi of hydrogengas with sufficient shaking to insure complete dispersion of thecatalyst. The nitrogen purged solution is then filtered through Celite™to remove the catalyst. The filtrate is concentrated in vacuo to affordthe desired product.

Prophetic Example 7 Synthesis of a Biocompatible Biodegradable Polymeras Disclosed Herein

The following is a prophetic example of the synthesis of thebiocompatible biodegradable polymer —[—NH-[VPGVG]₅-CO₂CH(CH₃)CO-]_(z)-.A solution of H₂N-[VPGVG]₅-CO₂CH(CH₃)CO₂H (1 g) in THF is stirred for 4days at room temperature. The resulting solution is concentrated invacuo and the resulting material taken up in solvent and the averagemolecular weight is determined.

Prophetic Example 8 Synthesis of a Biocompatible Biodegradable Polymeras Disclosed Herein

Commercially available elastin is filtered and extracted with water. Thewater soluble fraction is then lyophilized and the peptide fractionobtained is used as the ECM-mimetic, Mim. The Mim portion is taken up inDMF. To this solution in portions is added a mixture of methyl lactateand 1,1′-carbonyldiimidazole (1:1) in DMF. The lactate solution is addeduntil the disappearance of the major original Mim peaks as monitored byHPLC. The resulting solution is partitioned between water and ethylacetate. The solvent is removed in vacuo and the residue taken up inaqueous THF. A 1M solution of LiOH is added based upon the amount ofmethyl lactate that was added in the previous step. The solution isneutralized and concentrated. The resulting slurry is filtered to removeany inorganic salts and the filtrate is lyophilized. The resulting solidis taken up in dioxane and heated at 40° C. for 1 week. The solution isconcentrated under high vacuum, taken up in water, filtered, and thefiltrate lyophilized to provide the desired polymer.

Example 9 Synthesis of a Biocompatible Biodegradable Polymer asDisclosed Herein

Scheme V outlines the synthesis of a biocompatible biodegradable poly(GVGVP) polymer.

Step 1: Preparation of PLG-NHS

To a single-neck reaction flask, HO-PLG-COOH 5.00 grams (MW 3200, 1.56mmol of —COOH group), EDC.HCl 2.995 grams (MW 191.7, 15.6 mmole),N-hydroxysuccinimide 1.798 grams (MW 115.09, 15.62 mmol) and 25 mL ofchloroform were added. The solid slowly dissolved. The clear solutionwas stirred at room temperature for 21 hours. The reaction mixture wasconcentrated by removing about 15 mL of chloroform under high vacuum.About 10 mL of chloroform was left in the flask. To this, 100 mL ofmethanol was added. The product precipitated. The mixture was stirredfor two hours. The supernatant was decanted followed by the addition of50 mL of fresh methanol. The mixture was stirred overnight. Thesupernatant was decanted. The solid in the flask was dried under highvacuum at 60° C. 4.15 grams of product PLG-NHS was obtained. The ¹H NMRindicates the molecular weight to be 3200 Da.

Prophetic Step 2: Preparation of PLG-GVGVP Conjugate

To a flask, 0.4 grams of GVGVP (MW 10 k, 4×10⁻⁵ mole), 1.28 grams ofPLG-NHS (MW 3200, determined by NMR, 4×10⁻⁴ mole), and 2 mL of anhydrousDMSO is added. The clear reaction mixture is stirred for 18 hours. Tothe reaction mixture, 22 mL of ethyl acetate is added. The precipitationof product should occur immediately. The reaction mixtures istransferred to a falcon tube and centrifuged for 20 minutes at 2000 rpmto separate the solid product. The supernatant is decanted and 10 mL offresh ethyl acetate is added followed by centrifugation. After decantingthe supernatant, the solid product is recovered and dried under highvacuum at 60° C. for 3 hours.

Prophetic Step 3: Polycondensation of PLG-GVGVP

To a flask, 0.52 g of the PLG-GVGVP, 62.μl of diisopropylcarbodiimide(4×10⁻⁵ mole), 47 mg (3.84×10⁻⁵ mole) dimethylaminopyridine, and 20 mLof anhydrous DMSO is added. The reaction mixture is stirred at roomtemperature for 44 hours. To the reaction mixture, 200 mL of ethylacetate is added. The reaction mixtures is transferred to the falcontubes and centrifuged for 20 minutes at 2000 rpm to separate the solidproduct. The supernatant is decanted and 10 mL of fresh ethyl acetate isadded. The mixture is stirred for 30 minutes. The mixture is centrifugedagain followed by the decantation of the supernatant. The solid productfrom the tube is dried under high vacuum overnight.

Prophetic Example 10 Coated Stent with Paclitaxel or Rapamycin

The disclosed biocompatible biodegradable polymers can be dissolved in asuitable solvent to which is added a bioactive agent. The agent can bedissolved or dispersed. Examples include paclitaxel or rapamycin. Forexample, a solution is prepared containing 1-5 wt % polymer in solvent.To this solution is added 1-5 wt % paclitaxel (based on total combinedweight drug and polymer). Alternatively, approximately 20-30 wt %rapamycin can be added to the polymer solution (based on total combinedweight drug and polymer). A cardiac stent is dipped into the polymersolution containing drug and then removed. The solvent is allowed to dryby evaporation under suitable temperature and pressure conditions toevaporate the solvent leaving behind a drug-containing polymer filmcoating. The result is a drug-eluting polymer-coated stent.Alternatively, the drug-polymer solution may be spray-coated on to thestent in order to prepare the drug-eluting polymer-coated stent.

Prophetic Example 11 Incorporation of Goserelin Acetate

The disclosed biocompatible biodegradable polymers can be dissolved in asuitable organic solvent system. To this solution is added 5 wt %goserelin acetate (a bioactive peptide). This polymer solution isemulsified under high-shear mixing into an aqueous solution containing 2wt % polyvinyl alcohol. The resulting oil-in-water suspension is thendiluted with additional water to extract the organic solvent from thedroplets thereby forming drug-containing polymer microparticles. Theseparticles are collected by filtration, washed, dried to formbiodegradable drug-containing microparticles.

Prophetic Example 12 Incorporation of Risperidone

The disclosed biocompatible biodegradable polymers in a dry powderedform can be admixed with dry drug powder to form a dry-blend of drug andpolymer. For example, risperidone is blended at a level of 5 wt % intothe polymer of the present invention. This blend is then extruded in theform of a 1-mm diameter extruded rod which is then cut to 1.5 cm lengthsto form individual dosage forms of an extruded rod implant.

Prophetic Example 13 Preparation of Thin Filaments

The disclosed biocompatible biodegradable polymers can be extruded intoa thin filament (approximate 75-100 micrometers in diameter). Thisfilament is then woven to prepare a gauze-like fabric. This fabric isthen cut to desired size and used as a wound-cover patch. Alternatively,the thin filament is used to prepare a non-woven felt approximately 0.5mm in thickness. This felt is cut to desired size and used as amedical/surgical space-filling packing material. Alternatively, the thinfilament is prepared containing a suitable quantity of bioactive agentwithin the filament (for example, 2-5 wt % local anesthetic or 1-5 wt %non-steroidal anti-inflammatory agent). This filament is then used toprepare a woven or non-woven fabric for various medical or surgicalapplications.

1. A biocompatible polymer comprising: a) one or more ECM-mimeticpeptides; and b) one or more biodegradable moieties, wherein themoieties do not comprise an amino acid or residue thereof; wherein thepolymer has a weight-average molecular weight of from about 1,000 Da toabout 2,000,000 Da.
 2. The polymer according to claim 1, having theformula:

wherein: Mim is the ECM-mimetic peptide and has the formula:-[Xaa-Xbb-Xcc-Xdd-Xee]_(x)- wherein Xaa, Xbb, Xcc, Xdd, and Xee are eachindependently an amino acid residue chosen from: i) glycine or aconservative substitution thereof, ii) valine or a conservativesubstitution thereof, and iii) proline or a conservative substitutionthereof, BioDeg is the non-amino acid or residue thereof containing oneor more biodegradable moieties; the index x is an integer from 1 to 30;the index y is an integer from 1 to 10; and the index z is an integerfrom 1 to
 2000. 3. The polymer according to claim 1, wherein theECM-mimetic peptide comprises residues of amino acids chosen fromalanine, γ-aminobutyric acid, 2-aminohexanoic acid, arginine,asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine,homoserine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, phenylgylcine, proline, serine, threonine, tryptophan,tyrosine, and valine.
 4. The polymer according to claim 1, wherein theone or more ECM-mimetic peptides are chosen from: i)Val-Pro-Gly-Val-Gly; ii) Val-Pro-Gly-Gly-Val; iii) Val-Pro-Val-Gly-Gly;iv) Gly-Pro-Gly-Val-Val; v) Gly-Pro-Val-Gly-Val; vi)Gly-Pro-Val-Val-Gly; vii) Pro-Val-Gly-Val-Gly; viii)Pro-Val-Gly-Gly-Val; ix) Pro-Val-Val-Gly-Gly; x) Pro-Gly-Gly-Val-Val;xi) Pro-Gly-Val-Gly-Val; xii) Pro-Gly-Val-Val-Gly; xiii)Val-Gly-Pro-Val-Gly; xiv) Val-Gly-Pro-Gly-Val; xv) Val-Val-Pro-Gly-Gly;xvi) Gly-Gly-Pro-Val-Val; xvii) Gly-Val-Pro-Gly-Val; xviii)Gly-Val-Pro-Val-Gly; xix) Val-Gly-Val-Pro-Gly; xx) Val-Gly-Gly-Pro-Val;xxi) Val-Val-Gly-Pro-Gly; xxii) Gly-Gly-Val-Pro-Val; xxiii)Gly-Val-Gly-Pro-Val; xxiv) Gly-Val-Val-Pro-Gly; xxv)Val-Gly-Val-Gly-Pro; xxvi) Val-Gly-Gly-Val-Pro; xxvii)Val-Val-Gly-Gly-Pro; xxviii) Gly-Gly-Val-Val-Pro; xxix)Gly-Val-Gly-Val-Pro; and xxx) Gly-Val-Val-Gly-Pro.
 5. The polymeraccording to claim 1, wherein the one or more biodegradable moietiescomprise a hydroxy acid or a residue thereof.
 6. The polymer accordingto claim 1, wherein the one or more biodegradable moieties comprise oneor more residues of lactic acid, glycolic acid, lactide, glycolide,valerolactone, caprolactone, hydroxybutyrate, or a mixture thereof. 7.The polymer according to claim 1, wherein the one or more biodegradablemoieties comprise a residue of lactic acid or lactide.
 8. The polymeraccording to claim 1, wherein the one or more biodegradable moieties hasthe formula:

the index w is an integer from is from 0 to
 9. 9. The polymer accordingto claim 1, having the formula:

wherein R¹, R², R³, and R⁴ are each independently chosen from: viii)hydrogen; ix) —CH₃; x) —CH₂CH₃; xi) —CH₂CH₂CH₃; xii) —CH(CH₃)₂; xiii)—CH(CH₃)CH₂CH₃; and xiv) —CH₂CH₂CH(CH₃)₂; the index w is an integer from0 to 9; the index x is an integer from 1 to 30; and the index z is aninteger from 1 to
 2000. 10. The polymer according to claim 1, having theformula:

wherein R¹, R², R³, and R⁴ are each independently chosen from: i)hydrogen; ii) —CH₃; iii) —CH₂CH₃; iv) —CH₂CH₂CH₃; v) —CH(CH₃)₂; vi)—CH(CH₃)CH₂CH₃; and vii) —CH₂CH₂CH(CH₃)₂; the index w is an integer from0 to 9; the index x is an integer from 1 to 30; and the index z is aninteger from 1 to
 2000. 11. The polymer according to claim 1, having theformula:

wherein R¹, R², R³, and R⁴ are each independently chosen from: i)hydrogen; ii) —CH₃; iii) —CH₂CH₃; iv) —CH₂CH₂CH₃; v) —CH(CH₃)₂; vi)—CH(CH₃)CH₂CH₃; and vii) —CH₂CH₂CH(CH₃)₂; the index w is an integer from0 to 9; the index x is an integer from 1 to 30; and the index z is aninteger from 1 to
 2000. 12. The polymer according to claim 1, having theformula:

wherein R¹, R², R³, and R⁴ are each independently chosen from: i)hydrogen; ii) —CH₃; iii) —CH₂CH₃; iv) —CH₂CH₂CH₃; v) —CH(CH₃)₂; vi)—CH(CH₃)CH₂CH₃; and vii) —CH₂CH₂CH(CH₃)₂; the index w is an integer from0 to 9; the index x is an integer from 1 to 30; and the index z is aninteger from 1 to
 2000. 13. The polymer according to claim 1, having theformula:

wherein R¹, R², R³, and R⁴ are each independently chosen from: hydrogen;i) hydrogen; ii) —CH₃; iii) —CH₂CH₃; iv) —CH₂CH₂CH₃; v) —CH(CH₃)₂; vi)—CH(CH₃)CH₂CH₃; and vii) —CH₂CH₂CH(CH₃)₂; the index w is an integer from0 to 9; the index x is an integer from 1 to 30; and the index z is aninteger from 1 to
 2000. 14. The polymer according to claim 2, furthercomprising a biodegradable or non-biodegradable linker that links theone or more ECM-mimetic peptides to the one or more biodegradablemoieties.
 15. The polymer according to claim 14, having the formula:

wherein BioDeg is a residue of: i) lactic acid; ii) glycolic acid; iii)lactide; iv) glycolide; v) caprolactone; vi)hydroxybutyrate; vii)valerolactone; viii) a hydroxy acid; ix) a hydroxy fatty acid; x)lactide-co-glycolide; xi) lactide-co-caprolactone; xii)lactide-co-valerolactone; xiii) glycolide-co-caprolactone; xiv)glycolide-co-valerolactone; xv) lactide-co-glycolide-co-caprolactone; orxvi) lactide-co-glycolide-co-valerolactone; the index t is an integerfrom 1 to 10; the index y is an integer from 1 to 10; and the index z isan integer from 1 to
 2000. 16. The polymer according to claim 1, havingthe formula:[Xaa-Xbb-Xcc-Xdd-Xee]_(x)-[BioDeg]_(y) wherein: at least one of Xaa,Xbb, Xcc, Xdd, and Xee is a proline residue; the balance of Xaa, Xbb,Xcc, Xdd, and Xee are independently chosen from glycine, alanine,valine, leucine, and isoleucine; BioDeg comprises one or more residuesof lactide, glycolide, valerolactone, caprolactone, hydroxybutyrate, ormixtures thereof; the index x is an integer from 1 to 30; and the indexy is an integer from 1 to
 10. 17. The polymer according to claim 1,having a weight-average molecular weight of from about 1,000 Da to about2,000,000 Da.
 18. The polymer according to claim 1, having aweight-average molecular weight of from about 1,000 Da to about 20,000Da.
 19. The polymer according to claim 1, having a weight-averagemolecular weight of from about 10,000 Da to about 100,000 Da.
 20. Thepolymer according to claim 1, having a weight-average molecular weightof from about 100,000 Da to about 400,000 Da.
 21. The polymer accordingto claim 1, having a weight-average molecular weight of from about800,000 Da to about 2,000,000 Da.
 22. The polymer according to claim 1,having a weight-average molecular weight of from about 5000 Da to about20,000 Da.
 23. The polymer according to claim 1, having a weight-averagemolecular weight of from about 10,000 Da to about 20,000 Da.
 24. Thepolymer according to claim 1, having a weight-average molecular weightof from about 50,000 Da to about 2,000,000 Da.
 25. The polymer accordingto claim 16, wherein at least one of Xaa, Xbb, Xcc, Xdd, and Xee is avaline residue.
 26. The polymer according to claim 16, wherein at leastone of Xaa, Xbb, Xcc, Xdd, and Xee is a glycine residue.
 27. The polymeraccording to claim 2, wherein the conservative substitution for glycineis alanine.
 28. The polymer according to claim 2, wherein theconservative substitutions for valine is leucine or isoleucine.
 29. Thepolymer according to claim 1, having the formula:-[-[Xaa-Xbb-Xcc-Xdd-Xee]_(x)-[BioDeg]_(y)-]_(z)- wherein each Xaa, Xbb,Xcc, Xdd, and Xee is an amino acid residue; BioDeg comprises one or moreresidues of lactide, glycolide, valerolactone, caprolactone,hydroxybutyrate, or a mixture thereof; the index x is an integer from 1to 30; the index y is an integer from 1 to 10; and the index z is aninteger from 1 to 2,000.
 30. The polymer according to claim 29, whereinthe index z is an integer from 2 to
 6. 31. The polymer according toclaim 29, wherein the index z is an integer from 3 to
 5. 32. The polymeraccording to claim 29, wherein the index x is
 4. 33. The polymeraccording to claim 29, wherein the index x is
 5. 34. The polymeraccording to claim 29, wherein the index x is
 6. 35. The polymeraccording to claim 29, comprising an amino acid sequence having theformula chosen from: i) [Val-Pro-Gly-Val-Gly]_(x); ii)[Val-Pro-Gly-Gly-Val]_(x); iii) [Val-Pro-Val-Gly-Gly]_(x); iv)[Gly-Pro-Gly-Val-Val]_(x); v) [Gly-Pro-Val-Gly-Val]_(x); vi)[Gly-Pro-Val-Val-Gly]_(x); vii) [Pro-Val-Gly-Val-Gly]_(x); viii)[Pro-Val-Gly-Gly-Val]_(x); ix) [Pro-Val-Val-Gly-Gly]_(x); x)[Pro-Gly-Gly-Val-Val]_(x); xi) [Pro-Gly-Val-Gly-Val]_(x); xii)[Pro-Gly-Val-Val-Gly]_(x); xiii) [Val-Gly-Pro-Val-Gly]_(x); xiv)[Val-Gly-Pro-Gly-Val]_(x); xv) [Val-Val-Pro-Gly-Gly]_(x); xvi)[Gly-Gly-Pro-Val-Val]_(x); xvii) [Gly-Val-Pro-Gly-Val]_(x); xviii)[Gly-Val-Pro-Val-Gly]_(x); xix) [Val-Gly-Val-Pro-Gly]_(x); xx)[Val-Gly-Gly-Pro-Val]_(x); xxi) [Val-Val-Gly-Pro-Gly]_(x); xxii)[Gly-Gly-Val-Pro-Val]_(x); xxiii) [Gly-Val-Gly-Pro-Val]_(x); xxiv)[Gly-Val-Val-Pro-Gly]_(x); xxv) [Val-Gly-Val-Gly-Pro]_(x); xxvi)[Val-Gly-Gly-Val-Pro]_(x); xxvii) [Val-Val-Gly-Gly-Pro]_(x); xxviii)[Gly-Gly-Val-Val-Pro]_(x); xxix) [Gly-Val-Gly-Val-Pro]_(x); and xxx)[Gly-Val-Val-Gly-Pro]_(x); wherein the index x is an integer from 2 to6.
 36. The polymer according to claim 2, further comprising abiodegradable or non-biodegradable linker that links the BioDeg moietiesto the ECM-mimetic peptides.
 37. The polymer according to claim 36,having the formula:

wherein L is the biodegradable or non-biodegradable linker; BioDegcomprises one or more residues of lactide, glycolide, valerolactone,caprolactone, hydroxybutyrate, or copolymers thereof; y is an integerfrom 1 to 10; and z is an integer from 1 to
 2000. 38. The polymeraccording to claim 37, wherein the linker L is formed by the reaction ofMim and BioDeg with a linking reagent and wherein the linker L comprisesone or more chemical bonds chosen from: i) an alkyl; ii) an alkoxy; iii)a carbonyl; iv) a halogen comprising leaving group; v) an ester; vi) anorthoester; vii) an anhydride; viii) a phosphate; ix) a phosphazene; x)a phosphoester; xi) a dioxanaone; xii) a carbonate; xiii) anorthocarbonate; xiv) an amide; xv) an amine; xvi) an ester amide; xvii)a isocyanate; xviii) a urethane; xix) an etherester; xx) a pyrrolidone;or xxi) a unit comprising a combination of two or more units (i) to(xx).
 39. The polymer according to claim 37, wherein the linker has theformula:

and the index t is an integer from 1 to
 10. 40. The polymer according toclaim 37, wherein the linker has the formula:

and the index t is from 1 to
 10. 41. The polymer according to claim 37,wherein the linker has the formula:

and the index t is from 1 to
 10. 42. The polymer according to claim 37,wherein the linker has the formula:

and the index t is from 1 to
 10. 43. The polymer according to claim 37,wherein the linker has the formula:

and the index t is from 1 to
 10. 44. The polymer according to claim 37,wherein the linker has the formula:

and the index t is from 1 to
 10. 45. The polymer according to claim 37,wherein the linker has the formula:

and the index t is from 1 to
 10. 46. The polymer according to claim 1,wherein the one or more biodegradable moieties comprise one or morecrosslinking moieties that are crosslinked to another biodegradablepolymer.
 47. The polymer according to claim 1, wherein the one or moreECM-mimetic peptides comprise one or more crosslinking moieties that arecrosslinked to another ECM mimetic peptide.
 48. The polymer according toclaim 1, further comprising a bioactive agent.
 49. The polymer accordingto claim 1, wherein the one or more ECM-mimetic peptide comprises anelastin-mimetic, a fibrinogen-mimetic, a fibroin-mimetic, asilk-mimetic, a collagen-mimetic, a keratin-mimetic, or a mixturethereof.
 50. The polymer according to claim 2, wherein the one or morebiodegradable or non-biodegradable linker can be branched or may bemulti-functional so as to introduce branching the potential forperforming chemical crosslinking to the resulting polymer.
 51. Thepolymer according to claim 1, having the formula:

wherein the ECM-mimetic peptide Mim comprises 3 or more amino acidresidues having the formula: BioDeg is the non-amino acid residuecontaining biodegradable moiety; the index x is an integer from 1 to 30;the index y is an integer from 1 to 10; and the index z is an integerfrom 1 to
 2000. 52. The polymer according to claim 1, wherein theECM-mimetic peptide comprises an amino acid sequence having the formulachosen from: i) Val-Pro-Gly-Gly; ii) Xxx-Pro-Gly-Gly; iii)Ala-Pro-Gly-Val-Gly-Val; and iv) Gly-Ala-Gly-Ala-Gly-Ser; wherein Xxxrepresents any amino acid.
 53. A method for preparing a biocompatiblepolymer comprising: a) one or more ECM-mimetic peptides; b) one or morebiodegradable moieties, wherein the moieties do not comprise an aminoacid; wherein the polymer has an weight-average molecular weight of fromabout 1,000 Da to about 2,000,000 Da, comprising: a) providing anECM-mimetic peptide-comprising reagent having the formula:HN-Xaa-Xbb-Xcc-Xdd-Xee-OH  wherein Xaa, Xbb, Xcc, Xdd, and Xee are eachindependently an amino acid residue; b) coupling a biodegradable reagentthat does not comprise an α-amino acid to the ECM-mimetic peptide ofstep (a); and c) polymerizing the product of step (b).
 54. A method forpreparing a biocompatible polymer comprising: i) one or more ECM-mimeticpeptides; and ii) one or more biodegradable moieties, wherein themoieties do not comprise an amino acid; wherein the polymer has aweight-average molecular weight of from about 1,000 Da to about2,000,000 Da, comprising: a) providing an ECM-mimetic peptide-comprisingreagent having the formula:HN-(Xaa-Xbb-Xcc-Xdd-Xee)_(x)-OH  wherein Xaa, Xbb, Xcc, Xdd, and Xee areeach independently an amino acid residue, and the index x is an integerfrom 1 to 100; b) coupling a biodegradable reagent that does notcomprise an α-amino acid to the ECM-mimetic peptide of step (a); and c)polymerizing the product of step (b).
 55. An article comprising thebiocompatible polymer of claim
 1. 56. The article of claim 55, whereinthe article is a stent, implant, film, foam, sponge, patch, matrix,fabric, mesh, membrane, or felt.
 57. The article of claim 55, where inthe article is a stent that is coated with the biocompatible polymer.58. The article of claim 57, further comprising a bioactive agent.